Abstract
A plethora of evidence suggests that protein misfolding and aggregation are underlying mechanisms of various neurodegenerative diseases, such as prion diseases and Alzheimer’s disease (AD). Like prion diseases, AD has been considered as an infectious disease in the past decades as it shows strain specificity and transmission potential. Although it remains elusive how protein aggregation leads to AD, it is becoming clear that cellular prion protein (PrPC) plays an important role in AD pathogenesis. Here, we briefly reviewed AD pathogenesis and focused on recent progresses how PrPC contributed to AD development. In addition, we proposed a potential mechanism to explain why infectious agents, such as viruses, conduce AD pathogenesis. Microbe infections cause Aβ deposition and upregulation of PrPC, which lead to high affinity binding between Aβ oligomers and PrPC. The interaction between PrPC and Aβ oligomers in turn activates the Fyn signaling cascade, resulting in neuron death in the central nervous system (CNS). Thus, silencing PrPC expression may turn out be an effective treatment for PrPC dependent AD.
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Introduction
Alzheimer’s disease (AD), which was first reported by Dr. Alois Alzheimer in 1906 (Maurer et al. 1997), is a chronic neurodegenerative disease and one of the most common forms of dementia (Lane et al. 2018). In 2015, approximately 29.8 million AD patients were diagnosed worldwide, and it has been predicted that there will be more than 113 million AD patients worldwide by 2050 (Jellinger and Attems 2010; Vos et al. 2016). The incidence of AD is particularly high in the elderly; approximately 10% of people older than 60 years shows AD symptoms. In people older than 85 years, the prevalence is 50% (Gonsalves et al. 2012). Typical features of AD include short-term memory loss, visual-spatial perception disorders, and impairment of language and executive function (Pohanka 2018). The pathological features of AD include plaques formed by the deposition of amyloid β protein (Aβ) and neurofibrillary tangles formed by hyperphosphorylated tau protein (Glenner and Wong 1984; Lee et al. 1991; Martin et al. 2013; Ow and Dunstan 2014).
According to the time of onset, AD is classified as early-onset AD (EOAD) or late-onset AD (LOAD) (Bateman et al. 2011). EOAD, in which the age at onset is between 30 and 65 years, accounts for less than 0.1% of all AD cases (Blennow et al. 2006). LOAD, in which the age at onset is more than 65 years, is the most common form of AD. Both EOAD and LOAD can occur in people with a positive family history of AD; approximately 60% of patients with EOAD have multiple AD patients in their family, and 13% of these familial EOAD cases are inherited by autosomal dominant inheritance and affect at least three generations (Campion et al. 1999; Brickell et al. 2006). EOAD may also occur in LOAD families (Bird 2008). Only 1% to 5% of AD cases can be simply diagnosed genetically, whereas most AD cases are complex and may involve multiple susceptibility genes and their interactions with environmental factors (Serretti et al. 2005; Roses 2006; Reitz and Mayeux 2014).
In this review, we briefly reviewed the pathogenesis of AD with an emphasis on how cellular prion protein (PrPC) attribute to AD development. More importantly, we propose the interactions between PrPC and Aβ oligomers may be the underline mechanism for AD caused by other infectious agents, such as viruses. Finally, we point out potential studies to corroborate the role this interaction plays in vivo.
Factors Influencing AD Development
Even after many years of intensive research, the cause of AD is not completely understood. It is believed that 70% of risk is genetic and involves multiple genes (Ballard et al. 2011). In addition, other factors such as age and genders are also involved. Age is one of the most important factors affecting the pathogenesis of AD (Seshadri et al. 1997; Hebert et al. 2001). The incidence of AD increases significantly with age: 3% of people aged 65–74 years, 17% of people aged 75–84 years, and 32% of people of 85 years or older develop AD (Hebert et al. 2013). However, ageing perse does not cause AD. Gender is another important factor determining the risk of AD; more women than men suffer from AD (Mielke et al. 2014). However, as the average life expectancy of women is longer than that of men and as age is a big risk factor for AD, it is difficult to assign the effect only to gender. What confounds the effect of gender further is the observation that men aged 45–65 years have higher cardiovascular mortality than women (Chene et al. 2015). Because cardiovascular disease is a risk factor for AD (Kivipelto et al. 2006), men older than 65 years who do not have cardiovascular disease have a healthier cardiovascular condition, which reduces the risk of developing AD (Chene et al. 2015). In addition, environmental factors, such as air pollution or aluminum pollution, or personal habits, such as smoking, greatly influence the occurrence of AD (Markesbery and Ehmann 1993; McLachlan et al. 1992; Shin et al. 1995; Pratico et al. 2002; Banks et al. 2006; Zatta et al. 2009; Cataldo et al. 2010; Bolognin et al. 2011; Moulton and Yang 2012).
Genes Associated with AD
Various genes associated with AD have been identified to date, including genes encoding amyloid precursor protein (APP), presenilin-1 (PSEN-1), presenilin-2 (PSEN-2), CD2AP, apolipoprotein E (ApoE), clusterin (CLU), complement receptor 1 (CR1), prion protein (PRNP), and tumor necrosis factor (TNF) (Bertram et al. 2007; Carrasquillo et al. 2010; Corneveaux et al. 2010; Hooli et al. 2012; Krugeret al. 2012; Lambert et al. 2013; Sproul et al. 2014; Wang et al. 2016; Bi et al. 2018; Mukherjee et al. 2018; Rao et al. 2018; El Bitar et al. 2019).
ApoE has three alleles, ε2, ε3, and ε4, which encode ApoE2, ApoΕ3, and ApoE4, respectively. Among the three alleles, ε3 is the most common, whereas ε2 is the least common (Mahley and Rall 2000). People with the ε4 allele are more likely to develop AD than those with the ε2 or ε3 allele (Spinney 2014). It is estimated that people with one ε4 allele are three times more likely to develop AD than those with two ε3 alleles, whereas people with two ε4 alleles have a 8–12 times higher risk of developing AD (Holtzman et al. 2012; Loy et al. 2014). Comparing to those individuals having mutation in APP, PSEN-1, or PSEN-2, individuals expressing APOE-ε4 have slightly higher risk of developing AD (Chouraki and Seshadri 2014). Only 1% or less of AD cases are caused by mutation of APP, PSEN-1, or PSEN-2, which directly causes more Aβ42 production (Bekris et al. 2010), leading to Aβ oligomerization and consequently, neuron death. People with mutated APP or PSEN-1 will definitely develop AD if the mutations are AD-prone, whereas approximately 95% people with mutated PSEN-2 develop AD (Goldman et al. 2011).
Aggregated Proteins Contribute to AD
Like Aβ, α-synuclein, tau, and prion protein are aggregation-prone proteins that are implicated in AD.
α-Synuclein Cross-seeds Tau fibrillization, Contributing to AD Pathogenesis
α-Synuclein is the major structural component of Lewy body fibrils, however, it was originally identified in senile plaques as a non-Aβ component from AD brain (Ueda et al. 1993). α-Synuclein pathology has been reported in sporadic and familial cases of AD (Yokota et al. 2002; Willingham et al. 2003). The protein was first identified from Torpedo californica (Maroteaux et al. 1988). In humans, α-synuclein is encoded by the SNCA gene localized on chromosome 4. α-Synuclein is a 14.5-kDa protein and consists of 140 amino acids (Ueda et al. 1993; Xia et al. 2001). The mRNA of α-synuclein is selectively spliced to produce three isoforms, α-synuclein-140, α-synuclein-126, and α-synuclein-112. The most common is α-synuclein-140, which is the full transcript of the SNCA gene; α-synuclein-126 lacks residues 41–54 due to loss of exon 3; and α-synuclein-112 lacks residues 103–130 due to deletion of exon 5 (Ueda et al. 1994; Beyer 2006) (Fig. 1). α-Synuclein is abundant in the brain—it accounts for 1% of total proteins in the cytoplasm of brain cells (Iwai et al. 1995)—but is less abundant in the heart, muscles, and other tissues. In the brain, α-synuclein is mainly present at the tips of nerve cells at the presynaptic terminals (Iwai et al. 1995), where it interacts with phospholipids via its amino (N)-terminus (Clayton and George 1998; Chandra et al. 2003; Burre et al. 2012). In neurons, approximately 15% of α-synuclein is bound to the membrane, whereas the remainder is cytosolic, without a stable structure (McLean et al. 2000; Lee et al. 2002). Membrane-bound α-synuclein has amphipathic α-helix structures composed of 11 residues (XKTKEGVXXXX) (George et al. 1995; Weinreb et al. 1996; Kim 1997). α-Synuclein can interact with tubulin (Alim et al. 2002) and shows molecular chaperone activity to facilitate soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor (SNARE) complex formation (Chandra et al. 2005). Although cytosolicα-synuclein is unstructured and thus soluble, under pathological conditions α-synuclein can aggregate as insoluble fibrils, leading to Parkinson’s disease, Lewy body dementia, and multiple system atrophy, the pathological feature of Lewy body (Spillantini et al. 1997). Remarkably, different strains of synthetic α-synuclein fibrils showed significant differences in efficiency in cross-seeding tau aggregation in vitro and in vivo (Guo et al. 2013).
Schematic representation of the human SNCA gene. SNCA gene contains 6 exons, selectively spliced to produce three isoforms: α-synuclein-140, α-synuclein-126, and α-synuclein-112.
Hyperphosphorylated Tau Forms Neurofibrillary Tangles, Leading to AD
Identified in 1975, tau protein was first thought to be essential for microtubule assembly (Weingarten et al. 1975; Cleveland et al. 1977). The structure of tau is stabilized when the protein is bound to tubulin. Binding also hinders its phosphorylation. Human tau is encoded by the MAPT gene, which is located on chromosome 17q21 and is composed of 14 exons (Goedert et al. 1988, 1989). In the adult brain, tau mRNA is selectively spliced to produce six tau isomers composed of 352, 381, 383, 410, 412, and 441 amino acids, respectively (Buee et al. 2000) (Fig. 2). In neurons in the central nervous system, tau binds to tubulin via the positively charged carboxyl (C)-terminus to form microtubules. Besides promoting tubulin assembly, thus stabilizing microtubule structure, it also regulates synaptic synthesis and inter synaptic signal transmission (Iqbal et al. 2005).
Schematic representation of the human tau gene (modified from Buee et al. 2000). The human tau gene contains 14 exons, selectively spliced to produce six tau isomers composed of 352, 381, 383, 410, 412, and 441 amino acids, respectively.
Tau has 79 potential phosphorylation sites, and as much as 31 residues can be phosphorylated in tau protein (Billingsley and Kincaid 1997). In normal adult human brain, tau contains two to three phosphate groups per molecule. However, in AD, tau is 3–4-fold more phosphorylated than in control brains, leading to hyperphosphorylation containing approximately 8 mol PO4/mol tau (Kopke et al. 1993). The levels of total and phosphorylated tau in the cerebrospinal fluid are elevated in AD and correlate with a decrease in neuropsychological functions. Increased levels of phosphorylated tau protein threonine (t)181, t231, and total tau in the cerebrospinal fluid can be used to predict progression of mild cognitive impairment to AD (Mattsson et al. 2009). The extent of tau phosphorylation is regulated by protein kinase and phosphatase such as protein kinase A (PKA), protein kinase C (PKC), Ca2+/calmodulin-dependent kinase (CaM kinase) II, protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A) (Matsuo et al. 1994; Billingsley and Kincaid 1997; Taniguchi et al. 2001; Ballatore et al. 2007). Phosphorylated tau can dimerize in vivo, potentially leading to cross-linking and the formation of pairs of helical filaments. These pairs of helical filaments can compete with microtubules to bind normal tau and other macromolecular microtubule-associated proteins, leading to cytoskeletal abnormalities and axonal transport disorders, causing synaptic loss and finally leading to dementia (Alonso et al. 1997). Hyperphosphorylated tau accumulates to form neurofibrillary tangles, which are an important pathological feature of AD (Alonso et al. 1997; Martin et al. 2013) (Fig. 3).
Schematic representation of the process of Tau-induced neurofibrillary degeneration.
Amyloid Beta Can Form Aggregates Resulting in Neuron Damage in the Central Nervous System
The gene encoding APP is located on chromosome 21 in the human genome. APP is a transmembrane protein that can be processed via two pathways (Fig. 4). In the non-amyloid pathway, APP is cleaved by α-secretase between the 16th and 17th amino acids from the N-terminus to form soluble sAPPα and α-C-terminal fragments (α-CTFs). The α-CTF is further degraded by γ-secretase to produce P3 and incomplete Aβ (Aβ17–40 and Aβ17–42), which do not form amyloid deposits (Allinson et al. 2003). In the amyloid pathway, APP is cleaved by β-site amyloid precursor protein-cleaving enzyme 1, a transmembrane aspartyl protease that cleaves APP in the extracellular region to produce the N-terminus of Aβ, to form sAPPβ and β-C-terminal fragments (β-CTFs). The β-CTF is further cleaved by γ-secretase in the membrane to form the 3-kDa protein p3 and Aβ40 (major component) or Aβ42 (minor component) (Edbauer et al. 2003; Vassar 2004). Overexpression of APP in the brain of AD patients leads to the production of Aβ, which is cleaved by β-and γ-secretases (Masters et al. 1985). Aβ can exist as monomer, soluble oligomer, or insoluble fiber. Aβ monomer and insoluble Aβ fibers do not significantly change synaptic plasticity. However, soluble Aβ oligomers, including Aβ dimer and especially, OC antibody-positive oligomers from AD brain, can effectively impair synaptic structure and function (Shankar et al. 2008; Tomic et al. 2009). With ageing, the rate of Aβ production increases, whereas the rate of clearance decreases, resulting in Aβ deposition, which activates protein kinase II to hyperphosphorylate tau, resulting in tau aggregation and eventually leading to neurotoxicity and synaptic damage (Gotz et al. 2001; Jack et al. 2010; Falker et al. 2016).
Metabolic pathways of APP. A Non-amyloid pathway. APP is cleaved by α-secretase and γ-secretase to produce incomplete Aβ (Aβ17–40 and Aβ17–42). B Amyloid pathway. APP is cleaved by β-secretase and γ-secretase to produce Aβ40 or Aβ42.
PrPC-Bound Aβ Oligomers Lead to Loss of Neuron Plasticity
Although Aβ seems to play a central role in AD pathogenesis, it requires other molecules to cause neurotoxicity. One of these proteins is PrPC, a GPI-anchored glycoprotein located in lipid rafts in cell membranes (Yang et al. 2014). PrPC is highly conserved in mammals (Basler et al. 1986; Schatzl et al. 1997). The PRNP gene is a single-copy gene with one exon (Basler et al. 1986) localized on chromosome 20p13 in the human genome.
Similarities between AD and Prion Disease
Although criteria for the clinical diagnosis of AD have been clearly outlined, there is considerable overlap in the clinicopathological features of AD and prion disease, a rare neurodegenerative disease, which leads to difficulties in diagnosis (Watson 1979; Ball 1980; Masters et al. 1981; Brown et al. 1982; Van Everbroeck et al. 2004; Armstrong et al. 2005). In one study, more than half of patients who were diagnosed as having Creutzfeldt–Jakob disease were fully compliant with the criteria of AD (Tschampa et al. 2001). In addition, some subjects with hereditary prion diseases show obvious signs of AD (Ghetti et al. 1996; Zheng et al. 2008). Especially, patients without a family history of prion diseases can show clinical features similar to those of other neurodegenerative diseases, such as AD, in earlier phases (Kovacs et al. 2002). Like AD, most human prion diseases are sporadic and hereditary; less than 1% is acquired. Hereditary prion diseases with PRNP mutation account for 10%–15% of all prion diseases (Prusiner 1998; World Health Organization (WHO) 2003).
Misfolded Aβ Behaves as Prion
Besides clinicopathological similarity, Aβ and PrPSC (scrapie prion) share significant similarities at the molecular level. Like PrPSC, Aβ can aggregate to form oligomers, which can form insoluble amyloid fibers that form depositions (Sakono and Zako 2010). A synthetic Aβ with distinct morphology and molecular structure reportedly possessed self-propagating capability when seeded to grow fibrils (Petkova et al. 2005). In addition, Aβ aggregates are capable of self-propagation when inoculated into susceptible transgenic mice (Stohr et al. 2012), a character reminiscent of different prion strains (Jones and Surewicz 2005). Studies have also suggested that some cases of familial AD can be transmitted as prion disease. After supernatant of superior frontal gyrus or lateral orbital cortex homogenate from four AD patients or two neurologically normal controls was unilaterally injected into the right hippocampus and neocortex of 3-month-old male APP transgenic mice (Tg2576) for 5 months, the cerebral hemispheres injected with the AD supernatant, but not the control supernatant, formed a large number of senile plaques and vascular deposits formed by Aβ aggregation. Although Aβ deposits were the most concentrated in the injection area, some deposits appeared in areas far from the injection site, even along the corpus callosum in the contralateral hemisphere in some mice, indicating that Aβ had spread among and multiplied in cells, again a character reminiscent of PrPSC (Kane et al. 2000). Similarly, 10% of brain extracts from AD patients or brain lysates from Aβ-laden APP23 transgenic mice caused robust β-amyloid deposition in the hippocampus when injected into the hippocampus of young male APP23 mice (Cook and Austin 1978; Wisniewski et al. 1984; Kane et al. 2000; Meyer-Luehmann et al. 2006). More importantly, distinct Aβ strains can produce consistently different amyloid deposits when inoculated into bigenic mice. It has been shown that synthetic Aβ40 or Aβ42 strains, or brain lysates of “Arctic” or “Swedish” AD, which harbor E693G mutation or G670T/A671C double mutations, respectively, produced distinct but reproducible pathological attributes when inoculated into susceptible mice (Stohr et al. 2014; Watts et al. 2014; Watts and Prusiner 2018). These results strongly indicated that Aβ oligomers caused a transmission, but not a seeding effect.
Expression of PrPC is Required for AD Pathogenesis in Mice and Drosophila
Similarities in biophysical properties between Aβ and PrPSC, together with similarities in clinicopathological features between AD and prion disease suggest that these diseases share certain etiological mechanisms implicated in protein-misfolding diseases (Gajdusek 1994). In a transgenic AD mouse model, deletion of PRNP did not alter APP and Aβ expression levels, and astrocyte proliferation remained unchanged, with no axonal degeneration and synaptic loss. In contrast, AD transgenic mice with intact PrPC expression exhibited dysfunction and memory deficits. Transgenic mice lacking PrPC, but containing Aβ plaques showed no dysfunction and memory impairment (Gimbel et al. 2010). Treatment of aged APPswe/PSen1ΔE9 transgenic AD mice with anti-PrPC antibody restored synaptic density (Chung et al. 2010). In Drosophila, PrPC exacerbates AD pathogenesis (Younan et al. 2018). Thus, like prion disease, which requires PrPC to show neurotoxicity, PrPC is required for AD pathogenesis. These results suggest that PrPC plays an important role in mediating learning and memory deficits in the AD model.
PrPC Binds to Aβ
The requirement of PrPC expression in AD pathogenesis in the mouse and Drosophila models suggests a potential interaction between PrPC and Aβ. To investigate the mechanism of Aβ-mediated neuron toxicity, synthetic biotin-Aβ42 oligomers were used to screen binding partners on the surface of COS-7 cells expressing cDNAs from an adult mouse brain library (Lauren et al. 2009). It was found that PrPC expression was required for binding (Lauren et al. 2009). Further studies indicated that recombinant PrPC binds to soluble Aβ42 oligomers via two motifs, which span residues 23–27 and residues 95–110 (Calella et al. 2010; Chen et al. 2010; Fluharty et al. 2013; Younan et al. 2013; Ganzinger et al. 2014). However, it does not bind effectively to Aβ monomer and Aβ fibrils (Balducci et al. 2010; Chen et al. 2010). In fact, PrPC inhibits Aβ fiber formation by promoting Aβ oligomer stability (Younan et al. 2018). Unlike binding between recombinant small Aβ42 oligomers and PrPC, larger Aβ42 oligomers from AD brain lysate bind PrPC efficiently (Dohler et al. 2014; Haas et al. 2014; Kostylev et al. 2015), and this binding requires lipid raft integrity (Rushworth et al. 2013).
Aβ-affects PrPC-related Signaling Pathway
Binding between soluble Aβ42 oligomers and PrPC requires lipid rafts, the platform for cell signaling regulation (Simons and Toomre 2000; Mollinedo and Gajate 2015), suggesting that cellular signaling may be activated upon this binding. In neuron cells expressing PrPC, addition of Aβ oligomers activated synaptic cytoplasmic phospholipase A (2) to translocate into lipid rafts and to form a complex with PrPC and Aβ oligomers, leading to synapse damage (Bate and Williams 2011). The Src tyrosine kinase Fyn has been shown to colocalize with PrPC in lipid rafts, and aggregation of PrPC activates Fyn kinase in some cell lines (Pantera et al. 2009). When Aβ oligomers were added to PrPC-expressing neurons, they bound PrPC with high affinity, and activated Fyn (Thomas and Brugge 1997) to phosphorylate the NR2B subunit of the N-methyl-d-aspartate receptor, leading to its degradation (Um et al. 2012; You et al. 2012). Overexpression of Fyn enhanced Aβ-induced toxicity in a transgenic AD mouse model by inducing hyperphosphorylation of tau or neuronal Ca2+dyshomeostasis. Accordingly, when Fyn activity is inhibited, Aβ-induced damage can be reduced (Chin et al. 2005; Larson et al. 2012; De Mario et al. 2015). Another protein involved in Aβ oligomer-PrPC binding is the metabotropic glutamate receptor, mGluR5, a transmembrane protein in the postsynaptic density, which links Aβ oligomer-PrPC to Fyn. The addition of Aβ oligomers to neurons expressing PrPC and mGluR5 activates Fyn and calcium signaling to enhance eEF2 phosphorylation, leading to Arc translation and dendritic spine loss (Um et al. 2013) (Fig. 5).
Signaling cascades mediated by the interaction between PrPC and Aβ oligomers. A Binding between PrP and Aβ oligomers activates Fyn, which phosphorylates the NR2B subunit of the N-methyl-d-aspartate receptor, leading to its degradation. B An alternative pathway induced by PrP binding to Aβ oligomers, recruiting mGluR5, activating Fyn and leading to calcium accumulation and phosphorylation of eEF2, resulting in loss of neuron plasticity. The correlation between these two pathways remains to be determined.
PrPC-mediated Aβ Oligomer Inhibits Long-term Potentiation
Maintaining long-term potentiation (LTP) is widely accepted as one of the major cellular mechanisms that underlie learning and memory (Cooke and Bliss 2006). Soluble Aβ oligomers can inhibit LTP, leading to contraction of dendritic spines from pyramidal cells and causing spatial memory impairment. Hippocampal slices from PRNP null mice when tested for synaptic reactivity did not show Aβ oligomer-induced LTP damage (Lauren et al. 2009). Similarly, when binding between Aβ oligomers and PrPC was prevented by anti-PrPC antibodies, synaptic plasticity was rescued (Lauren et al. 2009). Remarkably, when administrated intracerebroventricularly, antibodies directed against the putative Aβ-binding site on PrPC prevented Aβ-mediated inhibition of LTP (Barry et al. 2011). In contrast, a Fab fragment directed against the PrPC region not involved in Aβ binding did not rescue LTP caused by Aβ oligomers (Barry et al. 2011).
Infectious Agents Activate PrPC Expression Associated with AD
In addition to Aβ–PrPC complex, many other factors contribute to AD pathogenesis, among which immune response and inflammation play critical roles (Sochocka et al. 2017). Infectious agents activate immune responses and inflammation; thus, it is not surprising that infectious agents have been suspected to play a role in AD (Himmelhoch et al. 1947; Cleobury et al. 1971; Lycke et al. 1974; Renvoize et al. 1979; Middleton et al. 1980; Renvoize and Hambling 1984; Wisniewski et al. 1984; Mirra et al. 1986; Mozar et al. 1987; Dittrich et al. 1989; Miklossy 1993; Miklossy et al. 1994, 2006; Balin et al. 1998; Price et al. 2001; Sauder et al. 2001; Riviere et al. 2002; Wojtowicz et al. 2002; Kountouras et al. 2006; Carbone et al. 2014; Schott 2015; McNamara and Murray 2016; Itzhaki 2017; Westman et al. 2017; Dominy et al. 2019). Herpes simplex virus (HSV) has been investigated extensively in AD (Sequiera et al. 1979; Jamieson et al. 1991, 1992; Itzhaki et al. 1997; Lin et al. 2002; Wozniak et al. 2005). In a HSV-infected mouse model, Aβ deposits were detected in the brain as a result of increased levels of β-site amyloid precursor protein-cleaving enzyme 1 in neuronal and glial cells (Wozniak et al. 2007). Although HSV-1 can also be detected in normal aged brain, in AD, infection by HSV-1 is restricted to particular regions, such as frontal and temporal cortices and the hippocampus, which suggests a causal relationship between HSV-1 infection and AD occurrence (Denaro et al. 2003). In addition, HSV-1 infection causes inflammatory cytokine IL-6 production, which may worsen AD (Luterman et al. 2000; Oshima et al. 2001). Finally, the presence of anti-HSV IgM indicates a reactivation of the infection, at which point the risk of developing AD is doubled (Lovheim et al. 2015). However, as the frequency of APOE ε4 is higher in AD patients with HSV-1 infection (Itzhaki et al. 1997; Corder et al. 1998), HSV-1 alone is not a risk factor for AD. Recently, human herpes virus-6A and-7 were found to be closely related to AD, possibly by regulating APP metabolism (Readhead et al. 2018). Interestingly, infection by Helicobacterpylori and human immunodeficiency virus (HIV) has been shown to upregulate the expression of PrPC (Muller et al. 1992; Konturek et al. 2005; Dohler et al. 2014), which has been implicated in inflammation (Pammer et al. 1998; de Almeida et al. 2005; Tsutsui et al. 2008; Hu et al. 2010; Gourdain et al. 2012; Petit et al. 2012; Ding et al. 2013; Liu et al. 2015; Wu et al. 2017). Thus, PrPC expression induced by infectious agents may contribute to neuron death by inducing an inflammation response. In addition, virus infection has been shown to induce Aβ deposition (Wozniak et al. 2007; Readhead et al. 2018), during which an interaction between Aβ oligomers and PrPC is possible. This interaction may initiate a signaling cascade leading to neuron apoptosis (Um et al. 2013).
Concluding Remarks and Perspectives
Multiple receptors for Aβ have been identified, among which PrPC shows the highest affinity. As PrPC itself is prone to oligomerization (Priola et al. 1995; Pan et al. 2005; Rambold et al. 2008; Gao et al. 2019), it remains to be investigated whether Aβ oligomers, when formed on the membrane of a neuron, bind to PrPC monomer or PrPC dimer first, as this may have implications for the activation of downstream signaling, thus affecting AD pathogenesis. Another issue that remains to be investigated is how posttranslational modification of PrPC affects its interaction with Aβ on a neuron. It is known that most PrPC on the cell surface has complex-type N-linked glycans, which prevent its oligomerization (Yi et al. 2018). It is unclear whether Aβ oligomers prefer non-glycosylated or glycosylated PrPC. Furthermore, cell-surface glycosaminoglycan (GAG) has been shown to recruit PrPC (Pan et al. 2002; Gao et al. 2016), thus forming a PrPC pool behaving as PrPC oligomers, whereas GAG also binds Aβ and is critical for Aβ fibril formation (Castillo et al. 1999). Interestingly, Aβ oligomers and GAG bind to the same motif on PrPC, but how GAG affects AD pathogenesis via modifying PrPC–Aβ interaction warrants further investigation.
By binding to PrPC, Aβ oligomers inhibit LTP, leading to cognitive decline in AD. Furthermore, the Aβ–PrPC oligomer complex can interact with the mGluR5 receptor, causing abnormal phosphorylation of eEF2 and resulting in loss of dendritic spines (Fig. 6).
Potential interactions between Aβ oligomers and PrPC on neurons. Left panel: in vivo, GAG might bind PrPC before Aβ oligomer formation. Aβ oligomers might replace GAG owing to its higher affinity for PrPC. Right panel: Aβ oligomers may bind PrPC monomer, GAG facilitates Aβ fibrilization by pulling PrPC monomer to oligomerize. In either case, N-linked glycans may resist PrPC oligomerization.
Besides binding to PrPC on neuronal cells, Aβ oligomers may also interact with PrPC on glia, which has been shown to be induced by HIV-1 infection. In the early stage of AD onset, activated microglia gather around Aβ plaques, producing neurotoxic molecules, such as NO, ROS, proteases, adhesion molecules, and pro-inflammatory cytokines TNF-α, IL-1β, IL-6 (Veerhuis et al. 2003; Trotta et al. 2014). Whether the binding of PrPC to Aβ oligomers has any role in generating neurotoxic molecules remains incompletely understood. Current data suggest that the interaction between Aβ and PrPC plays an important role in the pathophysiology of AD and might be a novel therapeutic target for of AD.
Aβ plaques occur many years before clinical symptoms can be detected. This suggests that either Aβ–PrPC complex requires a long time to form in vivo, or the threshold for triggering the signaling cascade to initiate AD in vivo is high. In addition, there is a variety of Aβ proteins, including Aβ37, Aβ38, Aβ40, Aβ42, and Aβ43, which can be further processed by aminopeptidase, glutaminyl cyclase or isomerase, and kinase (Kumar et al. 2011). How those modifications affect PrPC–Aβ oligomer interaction remains to be investigated.
Since binding between PrPC and Aβ oligomers plays an important role in ageing related AD and may also be responsible for infectious agents caused AD, understanding the interaction in vivo is of great importance for AD treatment.
References
Alim MA, Hossain MS, Arima K, Takeda K, Izumiyama Y, Nakamura M, Kaji H, Shinoda T, Hisanaga S, Ueda K (2002) Tubulin seeds alpha-synuclein fibril formation. J Biol Chem 277:2112–2117
Allinson TM, Parkin ET, Turner AJ, Hooper NM (2003) ADAMs family members as amyloid precursor protein alpha-secretases. J Neurosci Res 74:342–352
Alonso AD, Grundke-Iqbal I, Barra HS, Iqbal K (1997) Abnormal phosphorylation of tau and the mechanism of Alzheimer neurofibrillary degeneration: sequestration of microtubule-associated proteins 1 and 2 and the disassembly of microtubules by the abnormal tau. Proc Natl Acad Sci USA 94:298–303
Armstrong RA, Lantos PL, Cairns NJ (2005) Overlap between neurodegenerative disorders. Neuropathology 25:111–124
Balducci C, Beeg M, Stravalaci M, Bastone A, Sclip A, Biasini E, Tapella L, Colombo L, Manzoni C, Borsello T, Chiesa R, Gobbi M, Salmona M, Forloni G (2010) Synthetic amyloid-beta oligomers impair long-term memory independently of cellular prion protein. Proc Natl Acad Sci USA 107:2295–2300
Balin BJ, Gerard HC, Arking EJ, Appelt DM, Branigan PJ, Abrams JT, Whittum-Hudson JA, Hudson AP (1998) Identification and localization of Chlamydia pneumoniae in the Alzheimer’s brain. Med Microbiol Immunol 187:23–42
Ball MJ (1980) Features of Creutzfeldt–Jakob disease in brains of patients with familial dementia of Alzheimer type. Can J Neurol Sci 7:51–57
Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E (2011) Alzheimer’s disease. Lancet 377:1019–1031
Ballatore C, Lee VM, Trojanowski JQ (2007) Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci 8:663–672
Banks WA, Niehoff ML, Drago D, Zatta P (2006) Aluminum complexing enhances amyloid beta protein penetration of blood–brain barrier. Brain Res 1116:215–221
Barry AE, Klyubin I, Mc Donald JM, Mably AJ, Farrell MA, Scott M, Walsh DM, Rowan MJ (2011) Alzheimer’s disease brain-derived amyloid-beta-mediated inhibition of LTP in vivo is prevented by immunotargeting cellular prion protein. J Neurosci 31:7259–7263
Basler K, Oesch B, Scott M, Westaway D, Walchli M, Groth DF, McKinley MP, Prusiner SB, Weissmann C (1986) Scrapie and cellular PrP isoforms are encoded by the same chromosomal gene. Cell 46:417–428
Bate C, Williams A (2011) Amyloid-beta-induced synapse damage is mediated via cross-linkage of cellular prion proteins. J Biol Chem 286:37955–37963
Bateman RJ, Aisen PS, De Strooper B, Fox NC, Lemere CA, Ringman JM, Salloway S, Sperling RA, Windisch M, Xiong C (2011) Autosomal-dominant Alzheimer’s disease: a review and proposal for the prevention of Alzheimer’s disease. Alzheimers Res Ther 3:1
Bekris LM, Yu CE, Bird TD, Tsuang DW (2010) Genetics of Alzheimer disease. J Geriatr Psychiatry Neurol 23:213–227
Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE (2007) Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat Genet 39:17–23
Beyer K (2006) Alpha-synuclein structure, posttranslational modification and alternative splicing as aggregation enhancers. Acta Neuropathol 112:237–251
Bi R, Zhang W, Zhang DF, Xu M, Fan Y, Hu QX, Jiang HY, Tan L, Li T, Fang Y, Zhang C, Yao YG (2018) Genetic association of the cytochrome c oxidase-related genes with Alzheimer’s disease in Han Chinese. Neuropsychopharmacology 43:2264–2276
Billingsley ML, Kincaid RL (1997) Regulated phosphorylation and dephosphorylation of tau protein: effects on microtubule interaction, intracellular trafficking and neurodegeneration. Biochem J 323:577–591
Bird TD (2008) Genetic aspects of Alzheimer disease. Genet Med 10:231–239
Blennow K, de Leon MJ, Zetterberg H (2006) Alzheimer’s disease. Lancet 368:387–403
Bolognin S, Messori L, Drago D, Gabbiani C, Cendron L, Zatta P (2011) Aluminum, copper, iron and zinc differentially alter amyloid-Abeta(1-42) aggregation and toxicity. Int J Biochem Cell Biol 43:877–885
Brickell KL, Steinbart EJ, Rumbaugh M, Payami H, Schellenberg GD, Van Deerlin V, Yuan W, Bird TD (2006) Early-onset Alzheimer disease in families with late-onset Alzheimer disease: a potential important subtype of familial Alzheimer disease. Arch Neurol 63:1307–1311
Brown P, Salazar AM, Gibbs CJ Jr, Gajdusek DC (1982) Alzheimer’s disease and transmissible virus dementia (Creutzfeldt–Jakob disease). Ann N Y Acad Sci 396:131–143
Buee L, Bussiere T, Buee-Scherrer V, Delacourte A, Hof PR (2000) Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Brain Res Rev 33:95–130
Burre J, Sharma M, Sudhof TC (2012) Systematic mutagenesis of alpha-synuclein reveals distinct sequence requirements for physiological and pathological activities. J Neurosci 32:15227–15242
Calella AM, Farinelli M, Nuvolone M, Mirante O, Moos R, Falsig J, Mansuy IM, Aguzzi A (2010) Prion protein and Abeta-related synaptic toxicity impairment. EMBO Mol Med 2:306–314
Campion D, Dumanchin C, Hannequin D, Dubois B, Belliard S, Puel M, Thomas-Anterion C, Michon A, Martin C, Charbonnier F, Raux G, Camuzat A, Penet C, Mesnage V, Martinez M, Clerget-Darpoux F, Brice A, Frebourg T (1999) Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet 65:664–670
Carbone I, Lazzarotto T, Ianni M, Porcellini E, Forti P, Masliah E, Gabrielli L, Licastro F (2014) Herpes virus in Alzheimer’s disease: relation to progression of the disease. Neurobiol Aging 35:122–129
Carrasquillo MM, Belbin O, Hunter TA, Ma L, Bisceglio GD, Zou F, Crook JE, Pankratz VS, Dickson DW, Graff-Radford NR, Petersen RC, Morgan K, Younkin SG (2010) Replication of CLU, CR30, and PICALM associations with alzheimer disease. Arch Neurol 67:961–964
Castillo GM, Lukito W, Wight TN, Snow AD (1999) The sulfate moieties of glycosaminoglycans are critical for the enhancement of beta-amyloid protein fibril formation. J Neurochem 72:1681–1687
Cataldo JK, Prochaska JJ, Glantz SA (2010) Cigarette smoking is a risk factor for Alzheimer’s disease: an analysis controlling for tobacco industry affiliation. J Alzheimers Dis 19:465–480
Chandra S, Chen X, Rizo J, Jahn R, Sudhof TC (2003) A broken alpha-helix in folded alpha-Synuclein. J Biol Chem 278:15313–15318
Chandra S, Gallardo G, Fernandez-Chacon R, Schluter OM, Sudhof TC (2005) Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration. Cell 123:383–396
Chen S, Yadav SP, Surewicz WK (2010) Interaction between human prion protein and amyloid-beta (Abeta) oligomers: role OF N-terminal residues. J Biol Chem 285:26377–26383
Chene G, Beiser A, Au R, Preis SR, Wolf PA, Dufouil C, Seshadri S (2015) Gender and incidence of dementia in the Framingham Heart Study from mid-adult life. Alzheimers Dement 11:310–320
Chin J, Palop JJ, Puolivali J, Massaro C, Bien-Ly N, Gerstein H, Scearce-Levie K, Masliah E, Mucke L (2005) Fyn kinase induces synaptic and cognitive impairments in a transgenic mouse model of Alzheimer’s disease. J Neurosci 25:9694–9703
Chouraki V, Seshadri S (2014) Genetics of Alzheimer’s disease. Adv Genet 87:245–294
Chung E, Ji Y, Sun Y, Kascsak RJ, Kascsak RB, Mehta PD, Strittmatter SM, Wisniewski T (2010) Anti-PrPC monoclonal antibody infusion as a novel treatment for cognitive deficits in an Alzheimer’s disease model mouse. BMC Neurosci 11:130
Clayton DF, George JM (1998) The synucleins: a family of proteins involved in synaptic function, plasticity, neurodegeneration and disease. Trends Neurosci 21:249–254
Cleobury JF, Skinner GR, Thouless ME, Wildy P (1971) Association between psychopathic disorder and serum antibody to herpes simplex virus (type 1). Br Med J 1:438–439
Cleveland DW, Hwo SY, Kirschner MW (1977) Purification of tau, a microtubule-associated protein that induces assembly of microtubules from purified tubulin. J Mol Biol 116:207–225
Cook RH, Austin JH (1978) Precautions in familial transmissible dementia: including familial Alzheimer’s disease. Arch Neurol 35:697–698
Cooke SF, Bliss TV (2006) Plasticity in the human central nervous system. Brain 129:1659–1673
Corder E, Lannfelt L, Mulder M (1998) Apolipoprotein E and herpes simplex virus 1 in Alzheimer’s disease. Lancet 352:1312–1313
Corneveaux JJ, Myers AJ, Allen AN, Pruzin JJ, Ramirez M, Engel A, Nalls MA, Chen K, Lee W, Chewning K, Villa SE, Meechoovet HB, Gerber JD, Frost D, Benson HL, O’Reilly S, Chibnik LB, Shulman JM, Singleton AB, Craig DW, Van Keuren-Jensen KR, Dunckley T, Bennett DA, De Jager PL, Heward C, Hardy J, Reiman EM, Huentelman MJ (2010) Association of CR46, CLU and PICALM with Alzheimer’s disease in a cohort of clinically characterized and neuropathologically verified individuals. Hum Mol Genet 19:3295–3301
de Almeida CJ, Chiarini LB, da Silva JP, E Silva PM, Martins MA, Linden R (2005) The cellular prion protein modulates phagocytosis and inflammatory response. J Leukoc Biol 77:238–246
De Mario A, Castellani A, Peggion C, Massimino ML, Lim D, Hill AF, Sorgato MC, Bertoli A (2015) The prion protein constitutively controls neuronal store-operated Ca2+ entry through Fyn kinase. Front Cell Neurosci 9:416
Denaro FJ, Staub P, Colmer J, Freed DM (2003) Coexistence of Alzheimer disease neuropathology with herpes simplex encephalitis. Cell Mol Biol (Noisy-le-grand) 49:1233–1240
Ding T, Zhou X, Kouadir M, Shi F, Yang Y, Liu J, Wang M, Yin X, Yang L, Zhao D (2013) Cellular prion protein participates in the regulation of inflammatory response and apoptosis in BV2 microglia during infection with Mycobacterium bovis. J Mol Neurosci 51:118–126
Dittrich W, Bode L, Ludwig H, Kao M, Schneider K (1989) Learning deficiencies in Borna disease virus-infected but clinically healthy rats. Biol Psychiatry 26:818–828
Dohler F, Sepulveda-Falla D, Krasemann S, Altmeppen H, Schluter H, Hildebrand D, Zerr I, Matschke J, Glatzel M (2014) High molecular mass assemblies of amyloid-beta oligomers bind prion protein in patients with Alzheimer’s disease. Brain 137:873–886
Dominy SS, Lynch C, Ermini F, Benedyk M, Marczyk A, Konradi A, Nguyen M, Haditsch U, Raha D, Griffin C, Holsinger LJ, Arastu-Kapur S, Kaba S, Lee A, Ryder MI, Potempa B, Mydel P, Hellvard A, Adamowicz K, Hasturk H, Walker GD, Reynolds EC, Faull RLM, Curtis MA, Dragunow M, Potempa J (2019) Porphyromonas gingivalis in Alzheimer’s disease brains: evidence for disease causation and treatment with small-molecule inhibitors. Sci Adv 5:eaau3333
Edbauer D, Winkler E, Regula JT, Pesold B, Steiner H, Haass C (2003) Reconstitution of gamma-secretase activity. Nat Cell Biol 5:486–488
El Bitar F, Qadi N, Al Rajeh S, Majrashi A, Abdulaziz S, Majrashi N, Al Inizi M, Taher A, Al Tassan N (2019) Genetic study of Alzheimer’s disease in Saudi population. J Alzheimers Dis 67:231–242
Falker C, Hartmann A, Guett I, Dohler F, Altmeppen H, Betzel C, Schubert R, Thurm D, Wegwitz F, Joshi P, Verderio C, Krasemann S, Glatzel M (2016) Exosomal cellular prion protein drives fibrillization of amyloid beta and counteracts amyloid beta-mediated neurotoxicity. J Neurochem 137:88–100
Fluharty BR, Biasini E, Stravalaci M, Sclip A, Diomede L, Balducci C, La Vitola P, Messa M, Colombo L, Forloni G, Borsello T, Gobbi M, Harris DA (2013) An N-terminal fragment of the prion protein binds to amyloid-beta oligomers and inhibits their neurotoxicity in vivo. J Biol Chem 288:7857–7866
Gajdusek DC (1994) Spontaneous generation of infectious nucleating amyloids in the transmissible and nontransmissible cerebral amyloidoses. Mol Neurobiol 8:1–13
Ganzinger KA, Narayan P, Qamar SS, Weimann L, Ranasinghe RT, Aguzzi A, Dobson CM, McColl J, St George-Hyslop P, Klenerman D (2014) Single-molecule imaging reveals that small amyloid-beta1-42 oligomers interact with the cellular prion protein (PrP(C)). ChemBioChem 15:2515–2521
Gao Z, Zhang H, Hu F, Yang L, Yang X, Zhu Y, Sy MS, Li C (2016) Glycan-deficient PrP stimulates VEGFR2 signaling via glycosaminoglycan. Cell Signal 28:652–662
Gao Z, Shi J, Cai L, Luo M, Wong BS, Dong X, Sy MS, Li C (2019) Prion dimer is heterogenous and is modulated by multiple negative and positive motifs. Biochem Biophys Res Commun 509:570–576
George JM, Jin H, Woods WS, Clayton DF (1995) Characterization of a novel protein regulated during the critical period for song learning in the zebra finch. Neuron 15:361–372
Ghetti B, Piccardo P, Spillantini MG, Ichimiya Y, Porro M, Perini F, Kitamoto T, Tateishi J, Seiler C, Frangione B, Bugiani O, Giaccone G, Prelli F, Goedert M, Dlouhy SR, Tagliavini F (1996) Vascular variant of prion protein cerebral amyloidosis with tau-positive neurofibrillary tangles: the phenotype of the stop codon 145 mutation in PRNP. Proc Natl Acad Sci USA 93:744–748
Gimbel DA, Nygaard HB, Coffey EE, Gunther EC, Lauren J, Gimbel ZA, Strittmatter SM (2010) Memory impairment in transgenic Alzheimer mice requires cellular prion protein. J Neurosci 30:6367–6374
Glenner GG, Wong CW (1984) Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 120:885–890
Goedert M, Wischik CM, Crowther RA, Walker JE, Klug A (1988) Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. Proc Natl Acad Sci USA 85:4051–4055
Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA (1989) Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron 3:519–526
Goldman JS, Hahn SE, Catania JW, Larusse-Eckert S, Butson MB, Rumbaugh M, Strecker MN, Roberts JS, Burke W, Mayeux R, Bird T (2011) Genetic counseling and testing for Alzheimer disease: joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors. Genet Med 13:597
Gonsalves D, Jovanovic K, Da Costa Dias B, Weiss SF (2012) Global Alzheimer Research Summit: basic and clinical research: present and future Alzheimer research. Prion 6:7–10
Gotz J, Chen F, van Dorpe J, Nitsch RM (2001) Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science 293:1491–1495
Gourdain P, Ballerini C, Nicot AB, Carnaud C (2012) Exacerbation of experimental autoimmune encephalomyelitis in prion protein (PrPc)-null mice: evidence for a critical role of the central nervous system. J Neuroinflamm 9:25
Guo JL, Covell DJ, Daniels JP, Iba M, Stieber A, Zhang B, Riddle DM, Kwong LK, Xu Y, Trojanowski JQ, Lee VM (2013) Distinct alpha-synuclein strains differentially promote tau inclusions in neurons. Cell 154:103–117
Haas LT, Kostylev MA, Strittmatter SM (2014) Therapeutic molecules and endogenous ligands regulate the interaction between brain cellular prion protein (PrPC) and metabotropic glutamate receptor 5 (mGluR5). J Biol Chem 289:28460–28477
Hebert LE, Scherr PA, McCann JJ, Beckett LA, Evans DA (2001) Is the risk of developing Alzheimer’s disease greater for women than for men? Am J Epidemiol 153:132–136
Hebert LE, Weuve J, Scherr PA, Evans DA (2013) Alzheimer disease in the United States (2010–2050) estimated using the 2010 census. Neurology 80:1778–1783
Himmelhoch E, Latham O, Mc DC (1947) Alzheimer’s disease complicated by a terminal salmonella infection. Med J Aust 1:701–703
Holtzman DM, Herz J, Bu G (2012) Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease. Cold Spring Harb Perspect Med 2:a006312
Hooli BV, Mohapatra G, Mattheisen M, Parrado AR, Roehr JT, Shen Y, Gusella JF, Moir R, Saunders AJ, Lange C, Tanzi RE, Bertram L (2012) Role of common and rare APP DNA sequence variants in Alzheimer disease. Neurology 78:1250–1257
Hu W, Nessler S, Hemmer B, Eagar TN, Kane LP, Leliveld SR, Muller-Schiffmann A, Gocke AR, Lovett-Racke A, Ben LH, Hussain RZ, Breil A, Elliott JL, Puttaparthi K, Cravens PD, Singh MP, Petsch B, Stitz L, Racke MK, Korth C, Stuve O (2010) Pharmacological prion protein silencing accelerates central nervous system autoimmune disease via T cell receptor signalling. Brain 133:375–388
Iqbal K, Alonso Adel C, Chen S, Chohan MO, El-Akkad E, Gong CX, Khatoon S, Li B, Liu F, Rahman A, Tanimukai H, Grundke-Iqbal I (2005) Tau pathology in Alzheimer disease and other tauopathies. Biochim Biophys Acta 1739:198–210
Itzhaki RF (2017) Herpes simplex virus type 1 and Alzheimer’s disease: possible mechanisms and signposts. Faseb j 31:3216–3226
Itzhaki RF, Lin WR, Shang D, Wilcock GK, Faragher B, Jamieson GA (1997) Herpes simplex virus type 1 in brain and risk of Alzheimer’s disease. Lancet 349:241–244
Iwai A, Masliah E, Yoshimoto M, Ge N, Flanagan L, de Silva HA, Kittel A, Saitoh T (1995) The precursor protein of non-A beta component of Alzheimer’s disease amyloid is a presynaptic protein of the central nervous system. Neuron 14:467–475
Jack CR Jr, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, Petersen RC, Trojanowski JQ (2010) Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol 9:119–128
Jamieson GA, Maitland NJ, Wilcock GK, Craske J, Itzhaki RF (1991) Latent herpes simplex virus type 1 in normal and Alzheimer’s disease brains. J Med Virol 33:224–227
Jamieson GA, Maitland NJ, Wilcock GK, Yates CM, Itzhaki RF (1992) Herpes simplex virus type 1 DNA is present in specific regions of brain from aged people with and without senile dementia of the Alzheimer type. J Pathol 167:365–368
Jellinger KA, Attems J (2010) Prevalence of dementia disorders in the oldest-old: an autopsy study. Acta Neuropathol 119:421–433
Jones EM, Surewicz WK (2005) Fibril conformation as the basis of species-and strain-dependent seeding specificity of mammalian prion amyloids. Cell 121:63–72
Kane MD, Lipinski WJ, Callahan MJ, Bian F, Durham RA, Schwarz RD, Roher AE, Walker LC (2000) Evidence for seeding of beta-amyloid by intracerebral infusion of Alzheimer brain extracts in beta-amyloid precursor protein-transgenic mice. J Neurosci 20:3606–3611
Kim J (1997) Evidence that the precursor protein of non-A beta component of Alzheimer’s disease amyloid (NACP) has an extended structure primarily composed of random-coil. Mol Cells 7:78–83
Kivipelto M, Ngandu T, Laatikainen T, Winblad B, Soininen H, Tuomilehto J (2006) Risk score for the prediction of dementia risk in 20 years among middle aged people: a longitudinal, population-based study. Lancet Neurol 5:735–741
Konturek PC, Bazela K, Kukharskyy V, Bauer M, Hahn EG, Schuppan D (2005) Helicobacter pylori upregulates prion protein expression in gastric mucosa: a possible link to prion disease. World J Gastroenterol 11:7651–7656
Kopke E, Tung YC, Shaikh S, Alonso AC, Iqbal K, Grundke-Iqbal I (1993) Microtubule-associated protein tau. Abnormal phosphorylation of a non-paired helical filament pool in Alzheimer disease. J Biol Chem 268:24374–24384
Kostylev MA, Kaufman AC, Nygaard HB, Patel P, Haas LT, Gunther EC, Vortmeyer A, Strittmatter SM (2015) Prion-protein-interacting Amyloid-beta oligomers of high molecular weight are tightly correlated with memory impairment in multiple Alzheimer mouse models. J Biol Chem 290:17415–17438
Kountouras J, Tsolaki M, Gavalas E, Boziki M, Zavos C, Karatzoglou P, Chatzopoulos D, Venizelos I (2006) Relationship between Helicobacter pylori infection and Alzheimer disease. Neurology 66:938–940
Kovacs GG, Trabattoni G, Hainfellner JA, Ironside JW, Knight RS, Budka H (2002) Mutations of the prion protein gene phenotypic spectrum. J Neurol 249:1567–1582
Kruger J, Moilanen V, Majamaa K, Remes AM (2012) Molecular genetic analysis of the APP, PSEN1, and PSEN2 genes in Finnish patients with early-onset Alzheimer disease and frontotemporal lobar degeneration. Alzheimer Dis Assoc Disord 26:272–276
Kumar S, Rezaei-Ghaleh N, Terwel D, Thal DR, Richard M, Hoch M, Mc Donald JM, Wullner U, Glebov K, Heneka MT, Walsh DM, Zweckstetter M, Walter J (2011) Extracellular phosphorylation of the amyloid beta-peptide promotes formation of toxic aggregates during the pathogenesis of Alzheimer’s disease. EMBO J 30:2255–2265
Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, DeStafano AL, Bis JC, Beecham GW, Grenier-Boley B et al (2013) Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet 45:1452–1458
Lane CA, Hardy J, Schott JM (2018) Alzheimer’s disease. Eur J Neurol 25:59–70
Larson M, Sherman MA, Amar F, Nuvolone M, Schneider JA, Bennett DA, Aguzzi A, Lesne SE (2012) The complex PrP(c)-Fyn couples human oligomeric Abeta with pathological tau changes in Alzheimer’s disease. J Neurosci 32:16857–16871a
Lauren J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM (2009) Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature 457:1128–1132
Lee VM, Balin BJ, Otvos L Jr, Trojanowski JQ (1991) A68: a major subunit of paired helical filaments and derivatized forms of normal Tau. Science 251:675–678
Lee HJ, Choi C, Lee SJ (2002) Membrane-bound alpha-synuclein has a high aggregation propensity and the ability to seed the aggregation of the cytosolic form. J Biol Chem 277:671–678
Lin WR, Wozniak MA, Cooper RJ, Wilcock GK, Itzhaki RF (2002) Herpesviruses in brain and Alzheimer’s disease. J Pathol 197:395–402
Liu J, Zhao D, Liu C, Ding T, Yang L, Yin X, Zhou X (2015) Prion protein participates in the protection of mice from lipopolysaccharide infection by regulating the inflammatory process. J Mol Neurosci 55:279–287
Lovheim H, Gilthorpe J, Adolfsson R, Nilsson LG, Elgh F (2015) Reactivated herpes simplex infection increases the risk of Alzheimer’s disease. Alzheimers Dement 11:593–599
Loy CT, Schofield PR, Turner AM, Kwok JB (2014) Genetics of dementia. Lancet 383:828–840
Luterman JD, Haroutunian V, Yemul S, Ho L, Purohit D, Aisen PS, Mohs R, Pasinetti GM (2000) Cytokine gene expression as a function of the clinical progression of Alzheimer disease dementia. Arch Neurol 57:1153–1160
Lycke E, Norrby R, Roos BE (1974) A serological study on mentally ill patients with particular reference to the prevalence of herpes virus infections. Br J Psychiatry 124:273–279
Mahley RW, Rall SC Jr (2000) Apolipoprotein E: far more than a lipid transport protein. Annu Rev Genom Hum Genet 1:507–537
Markesbery W, Ehmann W (1993) Aluminum and Alzheimer’s disease. Clin Neurosci 1:212–218
Maroteaux L, Campanelli JT, Scheller RH (1988) Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J Neurosci 8:2804–2815
Martin L, Latypova X, Wilson CM, Magnaudeix A, Perrin ML, Yardin C, Terro F (2013) Tau protein kinases: involvement in Alzheimer’s disease. Ageing Res Rev 12:289–309
Masters CL, Gajdusek DC, Gibbs CJ Jr (1981) The familial occurrence of Creutzfeldt–Jakob disease and Alzheimer’s disease. Brain 104:535–558
Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K (1985) Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci USA 82:4245–4249
Matsuo ES, Shin RW, Billingsley ML, Van deVoorde A, O’Connor M, Trojanowski JQ, Lee VM (1994) Biopsy-derived adult human brain tau is phosphorylated at many of the same sites as Alzheimer’s disease paired helical filament tau. Neuron 13:989–1002
Mattsson N, Zetterberg H, Hansson O, Andreasen N, Parnetti L, Jonsson M, Herukka SK, van der Flier WM, Blankenstein MA, Ewers M, Rich K, Kaiser E, Verbeek M, Tsolaki M, Mulugeta E, Rosen E, Aarsland D, Visser PJ, Schroder J, Marcusson J, de Leon M, Hampel H, Scheltens P, Pirttila T, Wallin A, Jonhagen ME, Minthon L, Winblad B, Blennow K (2009) CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA 302:385–393
Maurer K, Volk S, Gerbaldo H (1997) Auguste D and Alzheimer’s disease. Lancet 349:1546–1549
McLachlan DR, Fraser PE, Dalton AJ (1992) Aluminium and the pathogenesis of Alzheimer's disease: a summary of evidence. Ciba Found Symp 169:87–98
McLean PJ, Kawamata H, Ribich S, Hyman BT (2000) Membrane association and protein conformation of alpha-synuclein in intact neurons. Effect of Parkinson’s disease-linked mutations. J Biol Chem 275:8812–8816
McNamara J, Murray TA (2016) Connections between herpes simplex virus type 1 and Alzheimer’s disease pathogenesis. Curr Alzheimer Res 13:996–1005
Meyer-Luehmann M, Coomaraswamy J, Bolmont T, Kaeser S, Schaefer C, Kilger E, Neuenschwander A, Abramowski D, Frey P, Jaton AL, Vigouret JM, Paganetti P, Walsh DM, Mathews PM, Ghiso J, Staufenbiel M, Walker LC, Jucker M (2006) Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science 313:1781–1784
Middleton PJ, Petric M, Kozak M, Rewcastle NB, McLachlan DR (1980) Herpes-simplex viral genome and senile and presenile dementias of Alzheimer and Pick. Lancet 1:1038
Mielke MM, Vemuri P, Rocca WA (2014) Clinical epidemiology of Alzheimer’s disease: assessing sex and gender differences. Clin Epidemiol 6:37–48
Miklossy J (1993) Alzheimer’s disease—a spirochetosis? NeuroReport 4:841–848
Miklossy J, Kasas S, Janzer RC, Ardizzoni F, Van der Loos H (1994) Further ultrastructural evidence that spirochaetes may play a role in the aetiology of Alzheimer’s disease. NeuroReport 5:1201–1204
Miklossy J, Kis A, Radenovic A, Miller L, Forro L, Martins R, Reiss K, Darbinian N, Darekar P, Mihaly L, Khalili K (2006) Beta-amyloid deposition and Alzheimer’s type changes induced by Borrelia spirochetes. Neurobiol Aging 27:228–236
Mirra SS, Anand R, Spira TJ (1986) HTLV-III/LAV infection of the central nervous system in a 57-year-old man with progressive dementia of unknown cause. N Engl J Med 314:1191–1192
Mollinedo F, Gajate C (2015) Lipid rafts as major platforms for signaling regulation in cancer. Adv Biol Regul 57:130–146
Moulton PV, Yang W (2012) Air pollution, oxidative stress, and Alzheimer’s disease. J Environ Public Health 2012:472751
Mozar HN, Bal DG, Howard JT (1987) Perspectives on the etiology of Alzheimer’s disease. JAMA 257:1503–1507
Mukherjee S, Mez J, Trittschuh EH, Saykin AJ, Gibbons LE, Fardo DW, Wessels M, Bauman J, Moore M, Choi SE, Gross AL, Rich J, Louden DKN, Sanders RE, Grabowski TJ, Bird TD, McCurry SM, Snitz BE, Kamboh MI, Lopez OL, De Jager PL, Bennett DA, Keene CD, Larson EB, Crane PK (2018) Genetic data and cognitively defined late-onset Alzheimer’s disease subgroups. Mol Psychiatry. https://doi.org/10.1038/s41380-018-0298-8
Muller WE, Pfeifer K, Forrest J, Rytik PG, Eremin VF, Popov SA, Schroder HC (1992) Accumulation of transcripts coding for prion protein in human astrocytes during infection with human immunodeficiency virus. Biochim Biophys Acta 1139:32–40
Oshima M, Azuma H, Suzutani T, Ikeda H, Okuno A (2001) Direct and mononuclear cell mediated effects on interleukin 6 production by glioma cells in infection with herpes simplex virus type 1. J Med Virol 63:252–258
Ow SY, Dunstan DE (2014) A brief overview of amyloids and Alzheimer’s disease. Protein Sci 23:1315–1331
Pammer J, Weninger W, Tschachler E (1998) Human keratinocytes express cellular prion-related protein in vitro and during inflammatory skin diseases. Am J Pathol 153:1353–1358
Pan T, Wong BS, Liu T, Li R, Petersen RB, Sy MS (2002) Cell-surface prion protein interacts with glycosaminoglycans. Biochem J 368:81–90
Pan T, Chang B, Wong P, Li C, Li R, Kang SC, Robinson JD, Thompsett AR, Tein P, Yin S, Barnard G, McConnell I, Brown DR, Wisniewski T, Sy MS (2005) An aggregation-specific enzyme-linked immunosorbent assay: detection of conformational differences between recombinant PrP protein dimers and PrP(Sc) aggregates. J Virol 79:12355–12364
Pantera B, Bini C, Cirri P, Paoli P, Camici G, Manao G, Caselli A (2009) PrPc activation induces neurite outgrowth and differentiation in PC12 cells: role for caveolin-1 in the signal transduction pathway. J Neurochem 110:194–207
Petit CS, Barreau F, Besnier L, Gandille P, Riveau B, Chateau D, Roy M, Berrebi D, Svrcek M, Cardot P, Rousset M, Clair C, Thenet S (2012) Requirement of cellular prion protein for intestinal barrier function and mislocalization in patients with inflammatory bowel disease. Gastroenterology 143:122–132.e115
Petkova AT, Leapman RD, Guo Z, Yau WM, Mattson MP, Tycko R (2005) Self-propagating, molecular-level polymorphism in Alzheimer’s beta-amyloid fibrils. Science 307:262–265
Pohanka M (2018) Oxidative stress in Alzheimer disease as a target for therapy. Bratisl Lek Listy 119:535–543
Pratico D, Uryu K, Sung S, Tang S, Trojanowski JQ, Lee VM (2002) Aluminum modulates brain amyloidosis through oxidative stress in APP transgenic mice. Faseb j 16:1138–1140
Price JL, Ko AI, Wade MJ, Tsou SK, McKeel DW, Morris JC (2001) Neuron number in the entorhinal cortex and CA1 in preclinical Alzheimer disease. Arch Neurol 58:1395–1402
Priola SA, Caughey B, Wehrly K, Chesebro B (1995) A 60-kDa prion protein (PrP) with properties of both the normal and scrapie-associated forms of PrP. J Biol Chem 270:3299–3305
Prusiner SB (1998) Prions. Proc Natl Acad Sci USA 95:13363–13383
Rambold AS, Muller V, Ron U, Ben-Tal N, Winklhofer KF, Tatzelt J (2008) Stress-protective signalling of prion protein is corrupted by scrapie prions. EMBO J 27:1974–1984
Rao S, Ghani M, Guo Z, Deming Y, Wang K, Sims R, Mao C, Yao Y, Cruchaga C, Stephan DA, Rogaeva E (2018) An APOE-independent cis-eSNP on chromosome 19q13.32 influences tau levels and late-onset Alzheimer’s disease risk. Neurobiol Aging 66:178.e171–178.e178
Readhead B, Haure-Mirande JV, Funk CC, Richards MA, Shannon P, Haroutunian V, Sano M, Liang WS, Beckmann ND, Price ND, Reiman EM, Schadt EE, Ehrlich ME, Gandy S, Dudley JT (2018) Multiscale analysis of independent Alzheimer’s Cohorts finds disruption of molecular, genetic, and clinical networks by human herpesvirus. Neuron 99:64–82.e67
Reitz C, Mayeux R (2014) Alzheimer disease: epidemiology, diagnostic criteria, risk factors and biomarkers. Biochem Pharmacol 88:640–651
Renvoize EB, Hambling MH (1984) Cytomegalovirus infection and Alzheimer’s disease. Age Ageing 13:205–209
Renvoize EB, Hambling MH, Pepper MD, Rajah SM (1979) Possible association of Alzheimer’s disease with HLA-BW15 and cytomegalovirus infection. Lancet 1:1238
Riviere GR, Riviere KH, Smith KS (2002) Molecular and immunological evidence of oral Treponema in the human brain and their association with Alzheimer’s disease. Oral Microbiol Immunol 17:113–118
Roses AD (2006) On the discovery of the genetic association of Apolipoprotein E genotypes and common late-onset Alzheimer disease. J Alzheimers Dis 9:361–366
Rushworth JV, Griffiths HH, Watt NT, Hooper NM (2013) Prion protein-mediated toxicity of amyloid-beta oligomers requires lipid rafts and the transmembrane LRP1. J Biol Chem 288:8935–8951
Sakono M, Zako T (2010) Amyloid oligomers: formation and toxicity of Abeta oligomers. FEBS J 277:1348–1358
Sauder C, Wolfer DP, Lipp HP, Staeheli P, Hausmann J (2001) Learning deficits in mice with persistent Borna disease virus infection of the CNS associated with elevated chemokine expression. Behav Brain Res 120:189–201
Schatzl HM, Da Costa M, Taylor L, Cohen FE, Prusiner SB (1997) Prion protein gene variation among primates. J Mol Biol 265:257
Schott JM (2015) Infection, inflammation and Alzheimer’s disease. Eur J Neurol 22:1503–1504
Sequiera LW, Jennings LC, Carrasco LH, Lord MA, Curry A, Sutton RN (1979) Detection of herpes-simplex viral genome in brain tissue. Lancet 2:609–612
Serretti A, Artioli P, Quartesan R, De Ronchi D (2005) Genes involved in Alzheimer’s disease, a survey of possible candidates. J Alzheimers Dis 7:331–353
Seshadri S, Wolf PA, Beiser A, Au R, McNulty K, White R, D’Agostino RB (1997) Lifetime risk of dementia and Alzheimer’s disease. The impact of mortality on risk estimates in the Framingham Study. Neurology 49:1498–1504
Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA, Rowan MJ, Lemere CA, Regan CM, Walsh DM, Sabatini BL, Selkoe DJ (2008) Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med 14:837–842
Shin RW, Lee VM, Trojanowski JQ (1995) Neurofibrillary pathology and aluminum in Alzheimer’s disease. Histol Histopathol 10:969–978
Simons K, Toomre D (2000) Lipid rafts and signal transduction. Nat Rev Mol Cell Biol 1:31–39
Sochocka M, Zwolinska K, Leszek J (2017) The infectious etiology of Alzheimer’s disease. Curr Neuropharmacol 15:996–1009
Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840
Spinney L (2014) Alzheimer’s disease: the forgetting gene. Nature 510:26–28
Sproul AA, Jacob S, Pre D, Kim SH, Nestor MW, Navarro-Sobrino M, Santa-Maria I, Zimmer M, Aubry S, Steele JW, Kahler DJ, Dranovsky A, Arancio O, Crary JF, Gandy S, Noggle SA (2014) Characterization and molecular profiling of PSEN1 familial Alzheimer’s disease iPSC-derived neural progenitors. PLoS ONE 9:e84547
Stohr J, Watts JC, Mensinger ZL, Oehler A, Grillo SK, DeArmond SJ, Prusiner SB, Giles K (2012) Purified and synthetic Alzheimer’s amyloid beta (Abeta) prions. Proc Natl Acad Sci USA 109:11025–11030
Stohr J, Condello C, Watts JC, Bloch L, Oehler A, Nick M, DeArmond SJ, Giles K, DeGrado WF, Prusiner SB (2014) Distinct synthetic Abeta prion strains producing different amyloid deposits in bigenic mice. Proc Natl Acad Sci USA 111:10329–10334
Taniguchi T, Kawamata T, Mukai H, Hasegawa H, Isagawa T, Yasuda M, Hashimoto T, Terashima A, Nakai M, Mori H, Ono Y, Tanaka C (2001) Phosphorylation of tau is regulated by PKN. J Biol Chem 276:10025–10031
Thomas SM, Brugge JS (1997) Cellular functions regulated by Src family kinases. Annu Rev Cell Dev Biol 13:513–609
Tomic JL, Pensalfini A, Head E, Glabe CG (2009) Soluble fibrillar oligomer levels are elevated in Alzheimer’s disease brain and correlate with cognitive dysfunction. Neurobiol Dis 35:352–358
Trotta T, Porro C, Calvello R, Panaro MA (2014) Biological role of Toll-like receptor-4 in the brain. J Neuroimmunol 268:1–12
Tschampa HJ, Neumann M, Zerr I, Henkel K, Schroter A, Schulz-Schaeffer WJ, Steinhoff BJ, Kretzschmar HA, Poser S (2001) Patients with Alzheimer’s disease and dementia with Lewy bodies mistaken for Creutzfeldt–Jakob disease. J Neurol Neurosurg Psychiatry 71:33–39
Tsutsui S, Hahn JN, Johnson TA, Ali Z, Jirik FR (2008) Absence of the cellular prion protein exacerbates and prolongs neuroinflammation in experimental autoimmune encephalomyelitis. Am J Pathol 173:1029–1041
Ueda K, Fukushima H, Masliah E, Xia Y, Iwai A, Yoshimoto M, Otero DA, Kondo J, Ihara Y, Saitoh T (1993) Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc Natl Acad Sci USA 90:11282–11286
Ueda K, Saitoh T, Mori H (1994) Tissue-dependent alternative splicing of mRNA for NACP, the precursor of non-A beta component of Alzheimer’s disease amyloid. Biochem Biophys Res Commun 205:1366–1372
Um JW, Nygaard HB, Heiss JK, Kostylev MA, Stagi M, Vortmeyer A, Wisniewski T, Gunther EC, Strittmatter SM (2012) Alzheimer amyloid-beta oligomer bound to postsynaptic prion protein activates Fyn to impair neurons. Nat Neurosci 15:1227–1235
Um JW, Kaufman AC, Kostylev M, Heiss JK, Stagi M, Takahashi H, Kerrisk ME, Vortmeyer A, Wisniewski T, Koleske AJ, Gunther EC, Nygaard HB, Strittmatter SM (2013) Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer abeta oligomer bound to cellular prion protein. Neuron 79:887–902
Van Everbroeck B, Dobbeleir I, De Waele M, De Deyn P, Martin JJ, Cras P (2004) Differential diagnosis of 201 possible Creutzfeldt–Jakob disease patients. J Neurol 251:298–304
Vassar R (2004) BACE1: the beta-secretase enzyme in Alzheimer’s disease. J Mol Neurosci 23:105–114
Veerhuis R, Van Breemen MJ, Hoozemans JM, Morbin M, Ouladhadj J, Tagliavini F, Eikelenboom P (2003) Amyloid beta plaque-associated proteins C1q and SAP enhance the Abeta1-42 peptide-induced cytokine secretion by adult human microglia in vitro. Acta Neuropathol 105:135–144
Vos T, Allen C, Arora M, Barber RM, Bhutta ZA, Brown A, Carter A, Casey DC, Charlson FJ, Chen AZ et al (2016) Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 388:1545–1602
Wang HZ, Bi R, Hu QX, Xiang Q, Zhang C, Zhang DF, Zhang W, Ma X, Guo W, Deng W, Zhao L, Ni P, Li M, Fang Y, Li T, Yao YG (2016) Validating GWAS-identified risk loci for Alzheimer’s disease in Han Chinese populations. Mol Neurobiol 53:379–390
Watson CP (1979) Clinical similarity of Alzheimer and Creutzfeldt–Jakob disease. Ann Neurol 6:368–369
Watts JC, Prusiner SB (2018) beta-amyloid prions and the pathobiology of Alzheimer’s disease. Cold Spring Harb Perspect Med 8:023507
Watts JC, Condello C, Stohr J, Oehler A, Lee J, DeArmond SJ, Lannfelt L, Ingelsson M, Giles K, Prusiner SB (2014) Serial propagation of distinct strains of Abeta prions from Alzheimer’s disease patients. Proc Natl Acad Sci USA 111:10323–10328
Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW (1975) A protein factor essential for microtubule assembly. Proc Natl Acad Sci USA 72:1858–1862
Weinreb PH, Zhen W, Poon AW, Conway KA, Lansbury PT Jr (1996) NACP, a protein implicated in Alzheimer’s disease and learning, is natively unfolded. Biochemistry 35:13709–13715
Westman G, Blomberg J, Yun Z, Lannfelt L, Ingelsson M, Eriksson BM (2017) Decreased HHV-6 IgG in Alzheimer’s disease. Front Neurol 8:40
Willingham S, Outeiro TF, DeVit MJ, Lindquist SL, Muchowski PJ (2003) Yeast genes that enhance the toxicity of a mutant huntingtin fragment or alpha-synuclein. Science 302:1769–1772
Wisniewski HM, Merz GS, Carp RI (1984) Senile dementia of the Alzheimer type: possibility of infectious etiology in genetically susceptible individuals. Acta Neurol Scand Suppl 99:91–97
Wojtowicz WM, Farzan M, Joyal JL, Carter K, Babcock GJ, Israel DI, Sodroski J, Mirzabekov T (2002) Stimulation of enveloped virus infection by beta-amyloid fibrils. J Biol Chem 277:35019–35024
World Health Organization (WHO) (2003) WHO manual for surveillance of human transmissible spongiform encephalopathies, including variant Creutzfeldt–Jakob disease. World Health Organization, Geneva
Wozniak MA, Shipley SJ, Combrinck M, Wilcock GK, Itzhaki RF (2005) Productive herpes simplex virus in brain of elderly normal subjects and Alzheimer’s disease patients. J Med Virol 75:300–306
Wozniak MA, Itzhaki RF, Shipley SJ, Dobson CB (2007) Herpes simplex virus infection causes cellular beta-amyloid accumulation and secretase upregulation. Neurosci Lett 429:95–100
Wu GR, Mu TC, Gao ZX, Wang J, Sy MS, Li CY (2017) Prion protein is required for tumor necrosis factor alpha (TNFalpha)-triggered nuclear factor kappaB (NF-kappaB) signaling and cytokine production. J Biol Chem 292:18747–18759
Xia Y, Saitoh T, Ueda K, Tanaka S, Chen X, Hashimoto M, Hsu L, Conrad C, Sundsmo M, Yoshimoto M, Thal L, Katzman R, Masliah E (2001) Characterization of the human alpha-synuclein gene: genomic structure, transcription start site, promoter region and polymorphisms. J Alzheimers Dis 3:485–494
Yang X, Zhang Y, Zhang L, He T, Zhang J, Li C (2014) Prion protein and cancers. Acta Biochim Biophys Sin (Shanghai) 46:431–440
Yi CW, Wang LQ, Huang JJ, Pan K, Chen J, Liang Y (2018) Glycosylation significantly inhibits the aggregation of human prion protein and decreases its cytotoxicity. Sci Rep 8:12603
Yokota O, Terada S, Ishizu H, Ujike H, Ishihara T, Nakashima H, Yasuda M, Kitamura Y, Ueda K, Checler F, Kuroda S (2002) NACP/alpha-synuclein, NAC, and beta-amyloid pathology of familial Alzheimer’s disease with the E184D presenilin-1 mutation: a clinicopathological study of two autopsy cases. Acta Neuropathol 104:637–648
You H, Tsutsui S, Hameed S, Kannanayakal TJ, Chen L, Xia P, Engbers JD, Lipton SA, Stys PK, Zamponi GW (2012) Abeta neurotoxicity depends on interactions between copper ions, prion protein, and N-methyl-d-aspartate receptors. Proc Natl Acad Sci USA 109:1737–1742
Younan ND, Sarell CJ, Davies P, Brown DR, Viles JH (2013) The cellular prion protein traps Alzheimer’s Abeta in an oligomeric form and disassembles amyloid fibers. Faseb j 27:1847–1858
Younan ND, Chen KF, Rose RS, Crowther DC, Viles JH (2018) Prion protein stabilizes amyloid-beta (Abeta) oligomers and enhances Abeta neurotoxicity in a Drosophila model of Alzheimer’s disease. J Biol Chem 293:13090–13099
Zatta P, Drago D, Bolognin S, Sensi SL (2009) Alzheimer’s disease, metal ions and metal homeostatic therapy. Trends Pharmacol Sci 30:346–355
Zheng L, Longfei J, Jing Y, Xinqing Z, Haiqing S, Haiyan L, Fen W, Xiumin D, Jianping J (2008) PRNP mutations in a series of apparently sporadic neurodegenerative dementias in China. Am J Med Genet B Neuropsychiatr Genet 147:938–944
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This work was supported by National Natural Science Foundation of China (31670170 and 31270209), by Ministry of Science and Technology of the People’s Republic of China (2018YFA0507201).
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Kong, C., Xie, H., Gao, Z. et al. Binding between Prion Protein and Aβ Oligomers Contributes to the Pathogenesis of Alzheimer’s Disease. Virol. Sin. 34, 475–488 (2019). https://doi.org/10.1007/s12250-019-00124-1
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DOI: https://doi.org/10.1007/s12250-019-00124-1