Abstract
We review the Alzheimer-related expression of genes following brain ischemia as risk factors for late-onset of sporadic Alzheimer’s disease and their role in Alzheimer’s disease ischemia-reperfusion pathogenesis. More recent advances in understanding ischemic etiology of Alzheimer’s disease have revealed dysregulation of Alzheimer-associated genes including amyloid protein precursor, β-secretase, presenilin 1 and 2, autophagy, mitophagy and apoptosis. We review the relationship between these genes dysregulated by brain ischemia and the cellular and neuropathological characteristics of Alzheimer’s disease. Here we summarize the latest studies supporting the theory that Alzheimer-related genes play an important role in ischemic brain injury and that ischemia is a needful and leading supplier to the onset and progression of sporadic Alzheimer’s disease. Although the exact molecular mechanisms of ischemic dependent neurodegenerative disease and neuronal susceptibility finally are unknown, a downregulated expression of neuronal defense genes like alfa-secretase in the ischemic brain makes the neurons less able to resist injury. The recent challenge is to find ways to raise the adaptive reserve of the brain to overcome such ischemic-associated deficits and support and/or promote neuronal survival. Understanding the mechanisms underlying the association of these genes with risk for Alzheimer’s disease will provide the most meaningful targets for therapeutic development to date.
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Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 2002;297:353–6.
Holtzman DM, Morris JC, Goate AM. Alzheimer’s disease: the challenge of the second century. Sci Transl Med 2011;3:77sr1.
Barra de la Tremblaye P, Plamondon H. Impaired conditioned emotional response and object recognition are concomitant to neuronal damage in the amygdale and perirhinal cortex in middle-aged ischemic rats. Behav Brain Res 2011;219:227–33.
Li J, Wang YJ, Zhang M, Fang CQ, Zhou HD. Cerebral ischemia aggravates cognitive impairment in a rat model of Alzheimer’s disease. Life Sci 2011;89:86–92.
Kiryk A, Pluta R, Figiel I, Mikosz M, Ułamek M, Niewiadomska G, et al. Transient brain ischemia due to cardiac arrest causes irreversible long-lasting cognitive injury. Behav Brain Res 2011;219:1–7.
Pluta R. The role of apolipoprotein E in the deposition of β-amyloid peptide during ischemia-reperfusion brain injury. A model of early Alzheimer’s disease. Ann NY Acad Sci 2000;903:324–34.
Pluta R. Astroglial expression of the beta-amyloid in ischemia-reperfusion brain injury. Ann NY Acad Sci 2002;977:102–8.
Pluta R, Ułamek M, Jabłoński M. Alzheimer’s mechanisms in ischemic brain degeneration. Anat Rec 2009;92:1863–81.
Pluta R, Jabłoński M, Czuczwar SJ. Postischemic dementia with Alzheimer phenotype: selectively vulnerable versus resistant areas of the brain and neurodegeneration versus β-amyloid peptide. Folia Neuropathol 2012;50:101–9.
Pluta R, Ułamek M, Januszewski S. Micro-blood-brain barrier openings and cytotoxic fragments of amyloid precursor protein accumulation in white matter after ischemic brain injury in long-lived rats. Acta Neurochir 2006;96(Suppl):267–71.
Pluta R, Januszewski S, Ułamek M. Ischemic blood-brain barrier and amyloid in white matter as etiological factors in leukoaraiosis. Acta Neurochir 2008;102(Suppl):353–6.
Sekeljic V, Bataveljic D, Stamenkovic S, Ułamek M, Jabłoński M, Radenovic L, et al. Cellular markers of neuroinflammation and neurogenesis after ischemic brain injury in the long-term survival rat model. Brain Struct Funct 2012;217:411–20.
Pluta R, Kida E, Lossinsky AS, Golabek AA, Mossakowski MJ, Wisniewski HM. Complete cerebral ischemia with shortterm survival in rats induced by cardiac arrest: I. Extracellular accumulation of Alzheimer’s β-amyloid protein precursor in the brain. Brain Res 1994;649:323–8.
Kida E, Pluta R, Lossinsky AS, Golabek AA, Choi-Miura NH, Wisniewski HM, et al. Complete cerebral ischemia with short-term survival in rat induced by cardiac arrest: II. Extracellular and intracellular accumulation of apolipoproteins E and J in the brain. Brain Res 1995;674:341–6.
Ishimaru H, Ueda K, Takahashi A, Maruyama Y. Changes in presynaptic protein NACP/alpha-synuclein in an ischemic gerbil hippocampus. Brain Res 1998;788:311–4.
Pluta R. Proteins associated with Alzheimer’s disease in conditions predisposing to Alzheimer’s-type neurodegeneration. J Cereb Blood Flow Metab 2001;21(Suppl. 1):S424.
Wen Y, Yang SH, Liu R, Perez EJ, Brun-Ziukemagel AM, Koulen P, et al. Cdk5 is involved in NFT-like tauopathy induced by transient cerebral ischemia in female rats. Biochim Biophys Acta 2007;1772:473–83.
Jendroska K, Poewe W, Daniel SE, Pluess J, Iwerssen-Schmidt H, Paulsen J, et al. Ischemic stress induces deposition of amyloid beta immunoreactivity in human brain. Acta Neuropathol 1995;90:461–6.
Wiśniewski HM, Maślińska D. Beta-protein immunoreactivity in the human brain after cardiac arrest. Folia Neuropathol 1996;34:65–71.
Jendroska K, Hoffmann OM, Amyloid Patt S. β peptide and precursor protein (APP) in mild and severe brain ischemia. Ann NY Acad Sci 1997;826:401–5.
Qi J, Wu H, Yang Y, Wand D, Chen Y, Gu Y, et al. Cerebral ischemia and Alzheimer’s disease: the expression of amyloid-β and apolipoprotein E in human hippocampus. J Alzheimers Dis 2007;12:335–41.
Maślińska D, Laure-Kamionowska M, Taraszewska A, Deręgowski K, Maśliński S. Immunodistribution of amyloid beta protein (Aβ) and advanced glycation end-product receptors (RAGE) in choroid plexus and ependyma of resuscitated patients. Folia Neuropathol 2011;49:295–300.
Pluta R. Experimental model of neuropathological changes characteristic for Alzheimer’s disease. Folia Neuropathol 1997;35:94–8.
Kim HS, Lee SH, Kim SS, Kim YK, Jeong SJ, Ma J, et al. Post-ischemic changes in the expression of Alzheimer’s APP isoforms in rat cerebral cortex. Neuroreport 1998;9:533–7.
Shi J, Panickar KS, Yang SH, Rabbani O, Day AL, Simpkins JW. Estrogen attenuates over-expression of beta-amyloid precursor protein messenger RNA in an animal model of focal ischemia. Brain Res 1998;810:87–92.
Shi J, Yang SH, Stubley L, Day AL, Simpkins JW. Hypoperfusion induces overexpression of β-amyloid precursor protein mRNA in a focal ischemic rodent model. Brain Res 2000;853:1–4.
Abe K, Tanzi RE, Kogure K. Selective induction of Kunitz-type protease inhibitor domain-containing amyloid precursor protein mRNA after persistent focal ischemia in rat cerebral cortex. Neurosci Lett 1991;125:172–4.
Koistinaho J, Pyykonen I, Keinanen R, Hokfelt T. Expression of β-amyloid precursor protein mRNAs following transient focal ischaemia. NeuroReport 1996;7:2727–31.
Kocki J, Ułamek-Kozioł M, Bogucka-Kocka A, Januszewski S, Jabłoński M, Gil-Kulik P, et al. Dysregulation of amyloid precursor protein, β-secretase, presenilin 1 and 2 genes in the rat selectively vulnerable CA1 subfield of hippocampus following transient global brain ischemia. J Alzheimers Dis 2015;47:1047–56.
Pluta R, Kocki J, Ułamek-Kozioł M, Petniak A, Gil-Kulik P, Januszewski S, et al. Discrepancy in expression of b-secretase and amyloid-β protein precursor in Alzheimer-related genes in the rat medial temporal lobe cortex following transient global brain ischemia. J Alzheimers Dis 2016;51:1023–31.
Yan FL, Zhang J, Guan XN, Hong Z. mRNA expression and activity of ADAM17 in hippocampus after chronic cerebral hypoperfusion: experiment with aged rats. Zhonghua Yi Xue Za Zhi 2007;87:2515–7.
Pluta R, Furmaga-Jabłońska W, Maciejewski R, Ułamek-Kozioł M, Jabłoński M. Brain ischemia activates β- and γ-secretase cleavage of amyloid precursor protein: significance in sporadic Alzheimer’s disease. Mol Neurobiol 2013;47:425–34.
Ye J, Pi R, Mao X, Chen X, Qin J, Xu S, et al. Alterations in mRNA expression of BACE1, cathepsin B, and glutaminyl cyclase in mice ischemic brain. Neuroreport 2009;20:1456–60.
Wolfe MS, Xia W, Ostaszewski BL, Diehl TS, Kimberly WT, Selkoe DJ. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature 1999;398:513–7.
Sastre M, Steiner H, Fuchs K, Capell A, Multhaup G, Condron MM, et al. Presenilin-dependent gamma secretase processing of beta-amyloid precursor protein at a site corresponding to the S3 cleavage of Notch. EMBO Rep 2001;2:835–41.
Polavarapu R, An J, Zhang C, Yepes M. Regulated intramembrane proteolysis of the low-density lipoprotein receptor-related protein mediates ischemic cell death. Am J Pathol 2008;172:1355–62.
Tanimukai H, Imaizumi K, Kudo T, Katayama T, Tsuda M, Takagi T, et al. Alzheimer-associated presenilin-1 gene is induced in gerbil hippocampus after transient ischemia. Mol Brain Res 1998;54:212–8.
Pennypacker KR, Hernandez H, Benkovic S, Morgan DG, Willing AE, Sanberg PR. Induction of presenilins in the rat brain after middle cerebral arterial occlusion. Brain Res Bull 1999;48:539–43.
Pluta R, Kocki J, Ułamek-Kozioł M, Bogucka-Kocka A, Gil-Kulik P, Januszewski S, et al. Alzheimer-associated presenilin 2 gene is dysregulated in rat medial temporal lobe cortex after complete brain ischemia due to cardiac arrest. Pharmacol Rep 2016;68:155–61.
Ułamek-Kozioł M, Kocki J, Bogucka-Kocka A, Petniak A, Gil-Kulik P, Januszewski S, et al. Dysregulation of autophagy, mitophagy and apoptotic genes in the medial temporal lobe cortex in an ischemic model of Alzheimer’s disease. J Alzheimers Dis 2016;54:113–21.
Hossmann KA, Schmidt-Kastner R, Grosse Ophoff B. Recovery of integrative central nervous function after one hour global cerebro-circulatory arrest in normothermic cat. J Neurol Sci 1987;77:305–20.
Jabłoński M, Maciejewski R, Januszewski S, Ułamek M, Pluta R. One year follow up in ischemic brain injury and the role of Alzheimer factors. Physiol Res 2011;60(Suppl. 1):S113–9.
Pluta R, Kocki J, Maciejewski R, Ułamek-Kozioł M, Jabłoński M, Bogucka-Kocka A, et al. Ischemia signaling to Alzheimer-related genes. Folia Neuropathol 2012;50:322–9.
Pluta R, Jabłoński M, Ułamek-Kozioł M, Kocki J, Brzozowska J, Januszewski S, et al. Sporadic Alzheimer’s disease begins as episodes of brain ischemia and ischemically dysregulated Alzheimer’s disease genes. Mol Neurobiol 2013;48:500–15.
Ishibashi S, Kuroiwa T, LiYuan S, Katsumata N, Li S, Endo S, et al. Long-term cognitive and neuropsychological symptoms after global cerebral ischemia in Mongolian gerbils. Acta Neurochir 2006;96(Suppl):299–302.
Cohan CH, Neumann JT, Dave KR, Alekseyenko A, Binkert M, Stransky K, et al. Effect of cardiac arrest on cognitive impairment and hippocampal plasticity in middle-aged rats. PLoS One 2015;10(5):e0124918.
Ułamek-Kozioł M, Pluta R, Bogucka-Kocka A, Januszewski S, Kocki J, Czuczwar SJ. Brain ischemia with Alzheimer phenotype dysregulates Alzheimer’s disease-related proteins. Pharmacol Rep 2016;68:582–91.
van Uden IW, van der Holst HM, van Leijsen EM, Tuladhar AM, van Norden AG, de Laat KF, et al. Late-onset depressive symptoms increase the risk of dementia in small vessel disease. Neurology 2016 in press.
Debette S, Markus HS. The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ 2010;341:c3666.
Bailey EL, McBride MW, Beattie W, McClure JD, Graham D, Dominiczak AF, et al. Differential gene expression in multiple neurological, inflammatory and connective tissue pathways in a spontaneous model of human small vessel stroke. Neuropathol Appl Neurobiol 2014;40:855–72.
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Ułamek-Kozioł, M., Pluta, R., Januszewski, S. et al. Expression of Alzheimer’s disease risk genes in ischemic brain degeneration. Pharmacol. Rep 68, 1345–1349 (2016). https://doi.org/10.1016/j.pharep.2016.09.006
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DOI: https://doi.org/10.1016/j.pharep.2016.09.006