History

Frau Auguste D was 51-years old, when on 25th November 1901 was admitted to the Municipal Mental Asylum in Frankfurt-am-Main, where, at that moment, Alois Alzheimer covered the position of senior physician. By the time Frau Auguste passed away, four years later, Dr Alzheimer was a co-worker to Dr Emil Kraepelin at the Anatomical Laboratory of the Royal Psychiatric Clinic, Munich University, where Frau Auguste D’s brain was sent for Alzheimer to perform the necroscopic exam, which he did on 8th April.

At the meeting of the South-West German Society of Alienists in Tűbingen, on the 3rd and 4th November 1906 Alois Alzheimer presented Frau Auguste D’s clinic-pathologic case; which subsequently published, on 1907, in the journal Allgemeine Zeitschrift für Psychiatrie und Psychisch-Gerichtliche Medizin.

“A woman, 51-years old, showed (...) increasing loss of memory (...) she would think that someone wanted to kill her (...). Periodically she was totally delirious, and seemed to have auditory hallucinations. (...) The generalised dementia progressed (...) After 4 years of the disease death occurred.”

At necroscopy Alzheimer found that brain was atrophic with atherosclerotic large vessels, and “peculiar changes of the neurofibrils (...) (were) clustering together in thick bundles which emerge (d) at the surface of the cell and miliary foci distinguishable by the deposit in the cerebral cortex of a peculiar substance (...) very refractory to staining” [1, 2]. The later so called neurofibrillary tangles and amyloid plaques, respectively. A year later, a second case was described by Francesco Bonfiglio (1883–1966), and two years later, Gaetano Perusini (1879–1915), published four cases: including the above two. Alzheimer, Bonfiglio, and Perusini did not realize yet they were facing a new disease, they thought of an unusual variant of senile dementia. It was Emil Kraepelin firstly to introduce the term Alzheimer’s disease, in the 8th edition of his textbook Compendium der Psychiatrie (1910) [2]. Until our days what has been mostly striking is that the certain diagnosis of Alzheimer’s disease could not have been made but post-mortem by the clinic-pathologic corollary reported in the Kraepelin’s Compendium der Psychiatrie referring mostly to Frau Auguste D’s Alzheimer’s case description; diagnosis depending on medical history, physical and neurological examinations, psychological testing, laboratory tests, brain imaging studies, and, possibly, brain tissue examination usually obtained at autopsy: namely too late!

Alzheimer’s disease is a frightening and shocking progressive neurodegenerative disorder clinically characterized by loss of memory and deficits in other cognitive domains and intellectual functions steadily developing [3], with the neurotransmitters which permit cells to be in touch with one another, including acetylcholine, somatostatin, monoamine and glutamate, lowered down. Such a scenario, characterized by damage to the neural networks critical for attention, memory, learning and higher cognitive abilities, possibly underlies the devastating symptomatology. Therefore, alterations in behaviour, such as apathy, agitation, and psychosis, are also fundamental characteristics [4]. Memory loss (amnesia), the most remarkable early symptom, usually introduces itself as minor forgetfulness, and then it becomes steadily more pronounced as the illness progresses; while possibly older memories keep on relatively preserved. As the disorder goes further, cognitive (intellectual) impairment extends to the domains of language (aphasia), coordinated movement (apraxia), recognition (agnosia) and to those functions (such as decision-making and planning) closely related to the frontal lobe of the brain, reflecting extension of the underlying pathological process. Neuronal loss, together with deposition of beta-amyloid plaques, in the spaces around synapses (neuritic plaques) [5], and abnormal accumulation of tau protein modified form in the cell bodies of neurons (neurofibrillary tangles) [3, 6] are the main features of the pathological process.

Many efforts have been made in the evaluation of the above stigmata by autopsy and the searching for a correlation with quantitative measures of dementia by the means of scales, such as the Blessed Dementia Scale [7–9]. Moreover, other scales have been used to quantify cognitive impairment, like the Mini Mental State Examination (MMSE) [10, 11], which have been used also to relate the cerebral ventricular size and the cerebrospinal fluid acetylcholinesterase levels with the degree of Alzheimer’s dementia disease [12]; or, also, the Assessment Scale for Cognition (ADAS-Cog) scores [13].

Disease mechanism(s)

Many efforts have been made in the understanding Alzheimer’s disease causes and mechanism(s). From time by time a mechanistic primum movens have been evoked for Alzheimer’s disease pathogenesis. It was 1965 when two different research groups have described experimentally induced Alzheimer’s disease like lesions in rabbit brains by aluminium exposure [14, 15]. Afterwards, it has been established that excessive cortical intranuclear aluminium content is present in Alzheimer’s disease patients, possibly relating to neurofibrillary degeneration [16–18]. Although the above observations arose into postulating aluminium neurotoxicity by induced immune-reactivity as etiologic issue in Alzheimer’s disease, such a mechanism has remained unconfirmed and therapies with chelating agents have been not advisable [19]. Another of the oldest hypotheses to elucidate the mechanism(s) underlying Alzheimer’s disease has been the “cholinergic” [20]. It is very well acknowledged the cholinergic neurotransmitter system quite critical role for the higher brain activities, such as the cognitive one [21]; besides, cholinergic neurons within the nucleus basalis of Meynert result nearly completely destroyed in Alzheimer’s disease [22]; therefore, subsequently many investigators have postulated the cholinergic dysfunction as the primary/direct memory decline causative in Alzheimer’s disease. Unfortunately, the first-generation Alzheimer’s therapeutic approaches based on the above hypothesis using mostly acetylcholinesterases inhibitors, have not led to a cure, but only to the transitory symptomatic palliative treatment [23] being cognitive enhancers still a provocative and vague label for drugs used to treat demented of the Alzheimer type [24], and the cholinergic network not the only one to be injured (see above). Two other hypotheses, more exquisitely interrelated with an “inflammatory” context, quite often have been alternatively described as the “baptist” and “tauist” viewpoints by Alzheimer’s disease dedicated scientific publications; stringently relating the beta-amyloid [5], and/or the tau proteins [25, 26] atypical physiopathology to the full disease cascade, respectively. Also Alpha synuclein, the protein involved in Parkinson’s disease, has been connected with amyloid plaques in Alzheimer’s disease [27]. Finally, pathological interactions among these three candidate proteins have been evoked [28, 29].

As a matter of fact, not all people who have pathologic classical Alzheimer’s disease stigmata, such as plaques and/or tangles, are clinically manifesting disease symptoms; being synapses loss much better related with the cognition decline than the mere presence of plaques and tangles [30, 31].

A great attention deal there have been regarding ‘oxygen radicals’, produced in an oxidative stress contest, as neurotoxic mediators processes behind Alzheimer’s and other neurodegenerative diseases stigmata [32–35], leading to the key role of anti-oxidants such as of vitamin E (tocopherol) in the nervous system and their possible use in treating the above diseases [36]. Thus, several studies have been performed in search of altered vitamin E concentrations in cortex [37, 38], in plasma [39], and also in cerebrospinal fluid of patients with Alzheimer’s disease [40, 41]. To date, disagreeing data do not sustain convincing vitamin E therapeutic effects on Alzheimer’s disease progression by itself. For example, the Alzheimer’s Disease Cooperative Study [42] showed that treatment with vitamin E could be helpful for a delay in the disease progression timing in moderately severe Alzheimer’s disease patients; while in another clinical study the results did not go in the same direction [43]. Discouraging results have been obtained also in clinical trials with Vitamin C (for which almost same antioxidant principles could apply) and/or vitamin E [44]. Although another attractive hypothesis to be mentioned is the “cobalaminergic” [45] elaborated by the low CSF and serum vitamin B12 levels evidences in Alzheimer’s patients [46, 47], vitamin B12 is biochemically, and nutritionally intimately related to folic acid [19], for which a specific chapter should be held. In fact, folates are essential for central nervous system development, and insufficient folate activity at the moment of conception and during early pregnancy can result in congenital neural tube defects. In adult life folate deficiency is often related to megaloblastic anaemia and, possibly, to high blood levels of homocysteine. Notably, elevated homocysteine blood levels, accompanied by low folate intake, have been linked with high arterial disease risk, but also with increased dementia and Alzheimer’s disease risks [48]. In fact, in Alzheimer’s disease experimental animal models folic acid deficiency homocysteine impairs DNA repair in hippocampal neurons and sensitize them to amyloid toxicity [49]. Furthermore, an Alzheimer’s dementia pathogenesis hypothesis has been related to the defective DNA repair ability in Alzheimer’s tissue cells, with consequential DNA damage, and cell functionality breakdown until death. Being cobalamin and folate dependently linked in a DNA and S-adenosylmethionine synthesis key position, cobalamin/folate deficiency (often featuring in Alzheimer’s disclosed disease) would result in a concomitant slow down DNA and S-adenosylmethionine synthesis, possible common pathogenesis hallmarks for Alzheimer’s disease, Down syndrome, and AIDS-related dementia [50].

In the stream of the redox failure, and, more in general, abnormalities in energy metabolism [51, 52], interest goes to the characterization of the mitochondrial injury [53], to the reduction of the key enzymes alpha-ketoglutarate dehydrogenase complex [54, 55], and carnitine acetyltransferase impairment [56], all leading to the clinical studies testing the therapeutic effects of acetyl-L-carnitine, which exerts also a cholinomimetic activity [57–64]. Noteworthy, it is remarkable to underline that, in Alzheimer’s disease patients who carry Apolipoprotein(Apo)E4 allele of APOE gene, the clinical Dementia Rating (CDR) score correlates better with alpha-ketoglutarate dehydrogenase enzyme complex activity than with densities of neuritic plaques or neuritic tangles; however, in patients without ApoE4, the CDR correlated better with densities of neuritic plaques or neuritic tangles than with alpha-ketoglutarate dehydrogenase enzyme complex activity [65]. This suggests that mitochondrial dysfunctions may be more important for the development of Alzheimer’s disease in patients who carry ApoE4 allele than in those who do not. ApoE, present in three common polymorphisms in the population: epsilon 2, epsilon 3, and epsilon 4, is a low density lipoprotein (LDL) associated lipoprotein involved in the plasmatic cholesterol transport and in the recognition by the LDL receptor; function which exerts also centrally where is involved in the brain cholesterol transport, has acquired very high importance for neurologists in 1993 when the association of the ApoE4 allele with familial and sporadic late-onset Alzheimer disease was reported [66–68]. ApoE involvement in Alzheimer’s disease is strongly related to cholesterol involvement into the physiopathology of the process beginning from the observation that levels of high-density lipoprotein cholesterol are significantly lower in multi-infarct dementia than in Alzheimer’s disease [69].

Cholesterol and ApoE

Cholesterol and apoE complex interplays are receiving greatest attention in Alzheimer’s disease involvement, as already extensively described elsewhere in reason of many experimental and clinical supporting data [70, 71]. Cholesterol in the brain is almost totally synthesized in loco [72]; it covers more than two percent of brain weight, and it covers about 25% of the total cholesterol body amount [73, 74]. The majority of cholesterol in central nervous system is unesterified and resides in two different pools: the myelin sheaths, and the plasma membranes of astrocytes and neurons. Brain cholesterol synthesis is very high during fetal development and declines in adult life being central cholesterol recycling quite efficient. In fact, in central nervous system cholesterol half-life could be as long as 5 years. But, still some excretion for central cholesterol steady state might be required. Thus, cholesterol exits the brain through the blood–brain barrier carried by ApoE or more properly by conversion into the polar oxisterol derivative 24(S)-hydroxycholesterol, also called cerebrosterol [75–77] to underline the fact that it is produced almost exclusively in the brain. 24(S)-hydroxycholesterol release into circulation reflects central cholesterol turnover with inverse age-dependent manner [78], then it could be considered a non-invasive marker for monitoring brain deregulated cholesterol turnover [79]. Not surprisingly, plasma (24(S)-hydroxycholesterol is very high in individuals with Alzheimer’s disease, as a consequence of the dramatic increased brain cholesterol turnover [80]. Remarkably, 24S-hydroxycholesterol induces inflammatory gene expression in primary human neural cells [81]; and, also it shows an in vitro neurotoxic profile [82]. Inversely, the other oxysterol 27-hydroxycholesterol mostly produced in non-brain tissues, such as the liver, might cross the blood–brain barrier in the opposite direction towards the brain where accumulate in Alzheimer’s disease patients [83].

The lipoproteins present in the cerebrospinal fluid, mostly represented by apoE [84, 85] function in brain cholesterol redistribution from producing cells, such as astrocytes, oligodendrocytes, and microglia to different cellular and subcellular sites of neurons [86] in the need of membrane remodelling during regeneration of neurites, axons, and synapses. ApoE is crucial for synaptic integrity by supplying cholesterol, stabilizing neural cytoskeleton, regulating intracellular calcium. ApoE is also a beta-amyloid scavenger by regulating extracellular beta-amyloid concentration through apoE receptor internalization to lysosomes. Increased neuronal cholesterol requirement for membrane regeneration induces glial apoE increased expression and secretion [87]. One of the 3 human isoforms of apoE, apoE4, is a very well documented risk factor for late-onset Alzheimer’s disease possibly because of the lower affinity for the apoE receptor with reduction of the beta-amyloid scavenging whit consequent increased beta-amyloid lipid peroxidation. Moreover, compared to ApoE3 ApoE4 is less expressed during increased brain cholesterol requirement affecting neurites, axons, and synapses regeneration until neural degeneration [71].

Beta-amyloid extracellular plaques formation occur preferentially in the cholesterol-rich regions of membranes known as lipid rafts, and cholesterol level changes might alter the distribution of beta-amyloid precursor cleaving enzymes within the membrane such as the integral membrane proteases (secretases) [88].

Interactions between insulin and cholesterol

Rafts may be involved in the aggregation of beta-amyloid and also in its clearance by amyloid-degrading enzymes such as plasmin, neprilysin [89]; and insulin-degrading enzyme [88]. Not surprisingly, clinical and epidemiological studies have found that type 2 diabetes, and hyperinsulinaemia, increase the risk of developing Alzheimer’s disease in the elderly. One of the links between hyperinsulinaemia and Alzheimer’s disease may be, among the others, insulin-degrading enzyme. Insulin-degrading enzyme degrades both insulin and amylin, peptides related to the pathology of type 2 diabetes, along with beta-amyloid. The current evidences suggest that hyperinsulinaemia may elevate beta-amyloid through insulin’s competition with beta-amyloid for insulin-degrading enzyme [88]. Genetic studies have also shown that insulin-degrading enzyme gene variations are associated with the clinical symptoms of Alzheimer’s disease as well as the risk of type 2 diabetes [88]. The deficiency of insulin-degrading enzyme can be caused by genetic variation or by the diversion of insulin-degrading enzyme from the metabolism of beta-amyloid to the metabolism of insulin [88]. It is intriguing to notice that both hyperinsulinaemia and insulin-degrading enzyme gene variations are related to the risk of Alzheimer’s disease when the Apolipoprotein E4 allele, the major risk factor of late-onset Alzheimer’s disease, is not present [70].

It is very important to keep in mind that insulin exerts a strong activity on 3-hydroxy-3-methylglutaryl-CoA reductase [90], the 3-hydroxy-3-methylglutaryl-CoA into mevalonate converting enzyme in the rate-limiting step in cholesterol biosynthesis. Interestingly, 3-hydroxy-3-methylglutaryl-CoA reductase cholesterol-lowering drugs (statins) that are 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors also act to stabilize and promote increased transcription and translation. Cholesterol is a feedback inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase and also reduces expression of the enzyme. Another important strong relationship between cholesterol and insulin is evident in type 2 diabetes, and more in general in insulin-resistance, where there is high synthesis of cholesterol with very low absorption [91, 92]. Insulin also down-regulates the expression of enzymes (cholesterol 7a-hydroxylase and sterol 27-hydroxylase) involved in the catabolism of cholesterol in oxysterols, which together with insulin are required for expression of sterol-regulatory-element-binding proteins [93]. Noteworthy, in Alzheimer’s disease patients are present altered levels of plasma oxysterols [82]. The sterol-regulatory-element-binding proteins modulate insulin’s ability to express genes involved in cholesterol and triacylglycerol synthesis. Finally, copper-oxidized LDL inhibits insulin-dependent phosphorylation of the signalling kinases ERK (extracellular-signal-regulated kinase) and PKB/Akt, suggesting that oxysterols may be involved in insulin resistance. For more specific details see ref [70].

Insulin functions in brain regions involved in cognition, and insulin dysfunction in these areas can result in memory loss and even Alzheimer’s disease [70, 94, 95]. In CNS there is high expression of insulin receptors mostly localized to synapses. The expression of insulin receptors, increased in postmortem brain tissues from patients with sporadic Alzheimer’s disease, shows a significant reduction in the kinase activity, suggesting an insulin signalling dysfunction in Alzheimer’s disease [96]. Consistent with this, a severe reduction in cerebral glucose utilization is found in late-onset sporadic Alzheimer’s disease, although their glucose supply to the brain is normal [97]. Also, it has been shown that the increase in blood insulin, not glucose level, significantly improves memory in Alzheimer’s disease, suggesting that insulin has a glucose-independent mechanism of regulating cognition [98]. Moreover, insulin and insulin-like growth factor I (IGF-I) (see below) are involved in tau phosphorylation. Old insulin receptor substrate 2 knockout mice show in the hippocampus neurofibrillary tangles deposits containing phosphorylated tau [98]. Insulin is a strong negative modulator of intracellular accumulation of beta-amyloid by accelerating beta-amyloid precursor protein/beta-amyloid transfer from Golgi to plasma membrane. Insulin degrading enzyme, the extracellular protease involved in insulin, IGF-I, and IGF-II degradation, as described above, is also involved in beta-amyloid cleavage. Not surprisingly, insulin degrading enzyme transgenic neuronal overexpressing mice present reduced brain beta-amyloid levels, and retarded or completely absent amyloid plaque formation; while, mice with insulin degrading enzyme deficit show increased cerebral accumulation of endogenous beta-amyloid [98].

Thus, insulin dysregulation may strongly contribute to Alzheimer’s disease pathology by several mechanisms, from reduced brain glucose utilization, to neurofibrillary tangle formation, and increased beta-amyloid aggregation by insulin degrading enzyme inhibition. Insulin effects on neuronal cognition and memory could act at several levels by regulating ion channels, neurotransmitter receptors and synaptic transmission. Being the memory improvement insulin-mediated very fast (∼30 min), it is quite possible an insulin receptor-mediated signal on substrates directly involved in synaptic transmission and plasticity, rather than targets that take much longer time to modify (e.g. beta-amyloid clearance) [98].

Given the above insulin activities, it is still very important to keep in mind that insulin, besides regulating glucose metabolism, stimulates lipogenesis, diminishes lipolysis, increases amino acid transport into cells, modulates transcription and stimulates growth, DNA synthesis and cell replication. Thus, distinguishing between insulin’s effects on glucose levels and insulin’s possible role as a neurohormone might be difficult, because changes in peripheral insulin produce a variety of effects unrelated to memory. For example, animals with streptozotocin-induced diabetes have impaired memory and insulin-enhancing therapeutic agents enhance memory [70].

Given relationship between non-insulin diabetes type 2 and Alzheimer’s disease [99], glucose itself has been shown to be toxic in several cell types such as endothelial [100], cardiomyocytes [101]; but also in critically ill patients with mortal effects [102]. It is already very well described ‘toxic’ effects of hyperglycaemia and the brain diabetic end-organ damage [99]. In fact, hyperglycaemic rodents, not only express cognitive impairments but also functional and structural alterations in the brain [103]. High glucose levels might exert toxic effects by an enhanced glucose flux through the polyol and hexosamine pathways, disturbances of intracellular second messenger pathways, an imbalance in the generation and scavenging of reactive oxygen species, and by advanced glycation of important structural and functional proteins. It is important also to underline how high glucose levels, as discussed above, might inhibit cholesterol intestinal absorbance, and increase cholesterol biosynthesis, peripherally [91, 92], and, possibly, centrally (brain).

Insulin and IGF-1

Emerging evidences underline the relationship between insulin and IGF-1 on important functions in the brain, such as on metabolic, neurotrophic, neuromodulatory and neuroendocrine activities. Also IGF-1, like insulin (see above), is present in brain by active transport through the blood–brain barrier and possibly by locally production in the brain. Insulin and IGF-1 share a high degree of structural and functional homology and both bind to, and activate the receptor of the other, thus sharing several physiological functions [104]. The insulin–IGF-1 pathway in Alzheimer’s disease shows perturbations overlapping with those above descript for insulin itself [94, 104], with IGF-1 also involved in the metabolism and clearance of beta-amyloid. Serum IGF-1 levels strictly relate with cerebral levels of beta-amyloid in animals: in old rats injected with IGF-1 beta-amyloid levels are decreased in the brain. While, in IGF-1 defective mice is present an increase in beta-amyloid cerebral levels. IGF-1 and insulin might also influence the development of neurofibrillary tangles by regulating the phosphorylation of tau as described elsewhere [104].

Metabolic system degeneration

Given all the above, when considering the involvement of single metabolic dysfunction and/or factor in Alzheimer’s dementia, many other metabolic pathways and factors should require to be taken into account for simultaneous/contemporaneous scientific investigations. Consequently, we might assist to the contours disclosure of predominant systemic metabolic dysfunctional representations in which Alzheimer’s disease is meant to play the tragic and horrifying leading role [105], contextualized to the above mentioned factors (plus many others) which participate and contribute in a (in)decorous way. Such an approach has been very useful in making an allowance for looking at Alzheimer’s disease as late-onset system degeneration, involving certain populations of cholinergic neurons but also many other cell populations. Thus, John P. Blass have been the enthusiastic protagonist, promoter, and catalyser of an outstanding scientific journey, spending most of his energies in searching, identifying and characterizing peripheral (nonneural) markers [106, 107] meant to be helpful for testing pathophysiological hypotheses and for the diagnosis of Alzheimer’s disease [108]. Accordingly, he has contributed, among others, to describe the reduced pyruvate dehydrogenase complex activity in Alzheimer brain and eventually in periferic fibroblasts [109, 110]; fibroblasts altered calcium uptake [111], changed metabolic properties [112], affected glucose metabolism [113], replicative life span [114], phosphofructokinase activity [115] compared to brain [116], expression of “Alzheimer antigens” [117], abnormality of the alpha-ketoglutarate dehydrogenase complex [118], altered oxidation and signal transduction systems [119]; red blood cell abnormalities [120], choline uptake [121]; the diminished mitogen-induced calcium uptake by lymphocytes [122]; the impairment of the mitochondrial function [123]; the reduced activities of thiamine-dependent enzymes in the brains and peripheral tissues [124]; transketolase abnormality [125]; brain carnitine, carnitine acetyltransferase, and glutathione [56], in Alzheimer’s disease patients; enriching the complex chapter of the metabolic alterations common to neural and non-neural cells in Alzheimer’s disease [126].

Multifactoriality and complexity

Alzheimer disease, like most chronic diseases, is probably best considered in a life course framework, with a journey started at patient’s conception and early foetal life. The epidemiological, preclinical, and clinical studies conducted over the past several decades strongly suggest that what lies beneath the disease, usually flaming much later in life [127], is a very slow chronic process involving risk factor constellations with neuropathologic alterations starting many decades before, at the lighting of the patient’s life [128, 129], in the stream of the thrifty phenotype hypothesis which claim the activation during the ontogenesis of adaptive mechanisms preventively activated in prevision of altered nutritional environment signalled by altered maternal nutrition [130]. For example, some risk factors such as genes inheritance and/or nutritional deprivation/excess altering brain formation and growth may have their major effects in early life; others related to socioeconomic status, such as smoking, malnutrition, and obesity in childhood, as well as in adulthood, may set the stage for later adulthood influences such as insulin resistance, obesity, hyperlipidemia, hypertension, diabetes, metabolic syndrome, cardiovascular, and cerebrovascular disease, all related to Alzheimer’s disease’s increased incidence [128–132].

Metabolic syndrome

The metabolic syndrome is characterized by clustering risk factors for cardiovascular diseases, but also for Alzheimer’s disease. Non insulin diabetes type 2 [99], hyperinsulinemia [133, 134], insulin resistance [135], atherosclerosis [136], inflammation, and inflammatory cytokines [137] have been identified as independent predictors of cerebrovascular disease, ischaemic stroke and accelerated cognitive decline and dementia, which, if combined, inside metabolic syndrome, might powerfully reinforce these effects [99]. Given the clustering of hyperinsulinemia, insulin resistance, hypertension, dyslipidaemia, hyperglicemia in metabolic syndrome the effort to determine which factor might be the primum movens in the development of Alzheimer’s disease cognitive dysfunction is becoming an empty exercise. Moreover, new evidences relate other factors, which are disrupted in the metabolic syndrome, with the cognitive impairment and Alzheimer’s disease development: leptin, adiponectin, and ghrelin.

Leptin

Adipose tissue secretes a variety of proteins with important roles in metabolism, reproduction, immunity and cardiovascular function. The endocrine function of adipose tissue, especially that exerted through leptin, could be simplistically linked to adaptive metabolic mechanisms to energy availability, leading to storage or mobilization of fat, in relationship to food intake and fasting energy storage providing insights into obesity and other diseases associated with energy imbalance [138, 139]. It is very important to underline the discovering of very well documented activities of leptin in the brain, with particular emphasis on transport across the blood–brain barrier, signal transduction, neuropeptide targets and roles during fasting and obesity [140]. In fact, leptin is released into the blood stream and circulates to the brain crossing the blood–brain barrier; to act through the leptin receptors (ObR), which is widely expressed in the central nervous system as multiple forms [141]. Leptin primarily acts on the hypothalamus arcuate nucleus neurons, but also hippocampal and peripheral neurons [142]. Very recent data disclose also the leptin involvement in memory function by synapses inducing mechanisms [143]. The CA1 hippocampal region of Zucker and db/db mice, neither of which expresses functional leptin receptors, shows impairments of long-term potentiation and long-term depression [144]. These mice present also impaired spatial memory further supporting an involvement of leptin and/or its receptor in Alzheimer’s disease. Spatial memory consolidation requires ERK activity in entorhinal cortex, a cerebral area affected by neurodegeneration in preclinical Alzheimer’s disease. Interestingly, leptin restores the increase in ERK1/2 phosphorylation which is lost in Leprdb/db mice pyriform and entorhinal cortex [145].

It has been also demonstrated leptin ability to regulate in vitro and in vivo beta-amyloid levels, the major proteinateous component of the amyloid plaques in Alzheimer’s disease patients’ brains. Leptin modulates beta-amyloid kinesis in a bidirectional way, reducing its extra-cellular levels, by reducing beta-secretase activity in neuronal cells possibly by altering the lipid composition of membrane lipid rafts; and by increasing apoE-dependent beta-amyloid uptake [146]. Finally, most strikingly, chronic administration of leptin to Alzheimer disease-transgenic animals reduces the brain beta-amyloid load [146]. Moreover, galanin, which together with its receptors (GALR) is overexpressed in limbic brain regions associated to cognition impairment in Alzheimer disease [147], results highly modulated in the mRNA expression by leptin [148]. Thus, a complex direct and indirect action in leptin deregulated conditions might be evoked in Alzheimer’s disease, taking into account also leptin involvement in the general metabolism with obvious consequences on the central nervous system (CNS) metabolism and performance.

As a matter of fact, a disturbed dual relationship between leptin and cortisol has been detected in Alzheimer’s patients [149], a weight loss associated to inappropriate leptin levels [150], or more related to gender dimorphism [151] probably due to the fact that the disease was already acclaimed at the leptin evaluation moments [152]; while, in some cases, the change in eating behaviour could be significantly more common in the frontotemporal dementia than in Alzheimer’s disease [153] or weight loss despite an increased intake of calories [154].

Ghrelin

Ghrelin, the endogenous ligand of growth hormone secretagogue (GHS) receptors, is gut hormone and neuropeptide, recognized for several years to influence pituitary hormone secretion, appetite, body weight, metabolism, and gastrointestinal, cardiovascular and immune systems, functions with a grossly direct and inverse relationship to adiponectin and leptin, respectively [155–160]. By looking at how ghrelin binds to parts of the brain that regulate food intake such as hippocampus, it has been found that it also binds to other parts like the pyramidal neuron of layer V in the sensorimotor area of cerebral cortex, in the cingulate gyrus, as well as in the neurons of lateral, paraventricular, and arcuate nuclei hypothalamus [161]. In Alzheimer’s, the hippocampus is the area that shows the most atrophy. It has also to be underlined the link between Alzheimer’s disease, as described elsewhere, and obesity, and insulin resistance and how obesity increases the progression of dementia, like in Alzheimer’s disease. Ghrelin binding is also present in other brain areas, including the telencephalon. Very recently it has been reported that circulating ghrelin going through the blood–brain barrier enters the hippocampus, and binding to neurons of the hippocampal formation promotes dendritic spine synapses formation and generation of long-term potentiation [162]. Ghrelin is highest in the circulation during the day and when the stomach is empty, these results also indicate that brain activity may be most effective before meal-time. The ghrelin-induced synaptic changes are paralleled by enhanced spatial learning and memory. Targeted disruption of the gene that encodes ghrelin results in decreased numbers of spine synapses in the CA1 region and impaired performance of mice in behavioural memory testing, both of which rapidly reversed by ghrelin administration [163]. Those observations disclose an endogenous/complex function of ghrelin linking once again metabolic activity controls with higher brain functions which when disrupted could disclose Alzheomer’s disease (-like symptoms).

Adiponectin

Adiponectin is, with (an inverse function compared to) leptin, another important adipocyte hormone involved in glucose and lipid metabolism generating a negative energy balance by increasing energy expenditure. Adiponectin, also known as Acrp30, is an adipose tissue-derived hormone with anti-atherogenic, anti-diabetic and insulin sensitizing properties [164–167]. In mice, targeted deletion of the adiponectin gene leads to insulin resistance [168, 169]. In addition, administration by continuous systemic infusion of adiponectin significantly increases insulin sensitivity in type 2 diabetic mice [170]. In humans, a reduced serum concentration of adiponectin has been shown to correlate with obesity [171], insulin resistance [171, 172] and type 2 diabetes [172–174]. Collectively, these findings suggest that adiponectin not only has an essential function in regulating whole-body energy homeostasis, but also it could strongly counteract the most of the risk factors for sporadic Alzheimer’s disease such as insulin resistance, diabetes, obesity, vascular injury, atherosclerosis, and, more in general the metabolic syndrome. It is possible that adiponectin’s protective effects could be played mostly indirectly due to the fact that neither radiolabelled nonglycosylated nor glycosylated globular adiponectin crosses the blood–brain barrier in mice; and, in addition, adiponectin is not detectable in human cerebrospinal fluid using various established methods. Interestingly, it has been shown adiponectin receptors expression in brain endothelium, upregulated during fasting [175]. The above phenomena might account for a further adiponectin (indirect) regulatory mechanism on brain metabolism-activity; regulatory mechanism probably affected in Alzheimer’s disease. In this sense, it is noticeable that treatment with adiponectin reduces secretion of the centrally active interleukin-6 (IL-6) [176] in the above brain endothelial cells, phenomenon paralleled by a similar trend of other proinflammatory cytokines. It is remarkable that IL-6, and proinflammatory cytokines, has not only been involved in immune dysfunction but also in Alzheimer’s disease pathogenesis [176].

Conclusions

In the ‘80s John P. Blass, by focusing his attention by a metabolic approach to the neurodegenerative diseases, made a cultural/scientific revolution in the understanding of Alzheimer’s disease. Only nowadays such an approach is reaching the critical mass useful for lightening a real revolution in the understanding the physiopathology of Alzheimer’s disease for an efficacious therapy which until now has been examined through the residual phenotype represented by a damaged brain.