MUHAMMET CEMAL KIZILARSLANOĞLU, ZEKERİYA ÜLGER

Role of autophagy in the pathogenesis of Alzheimer disease

Alzheimer disease (AD) is the most common progressive neurodegenerative disorder causing increased morbidity and mortality. It is characterized by accumulation of amyloid-β in neurons. As there is no known definitive treatment of this disorder, studies trying to determine its exact pathogenetic pathways and target therapies for these specific pathways are being rapidly conducted. Autophagy is one of the areas of interest in studies on the pathogenesis of AD. It is a process of self-digestion that is thought to be a response to stressors and allows cells to adapt to environmental changes. There is accumulating evidence showing an association between autophagy and some disorders like cancer, infectious disease, and, in particular, neurodegenerative disorders. Growing attention has been focused on impaired autophagy in neurodegenerative disorders including AD, resulting in buildup of toxic molecules because of inappropriate activation of proteases or defective proteolysis. The question of whether autophagic response may be precisely modulated to prevent or treat neurodegenerative disorders like AD is still unanswered. In the future, it is thought that the autophagic process may be the one of the cornerstones of the treatment of AD. In this review, we summarize the knowledge of autophagy in the pathogenesis of AD in light of the current literature.

Anahtar Kelimeler:

Autophagy, Alzheimer disease, neurodegenerative disorders

Role of autophagy in the pathogenesis of Alzheimer disease

Keywords:

Autophagy, Alzheimer disease, neurodegenerative disorders,

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Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, Raman R, Sun X, Aisen PS et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med 2014; 370: 311–321.
Salloway S, Sperling R, Fox NC, Blennow K, Klunk W, Raskind M, Sabbagh M, Honig LS, Porsteinsson AP, Ferris S et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med 2014; 370: 322–333.
Shintani T, Klionsky DJ. Autophagy in health and disease: a double-edged sword. Science 2004; 306: 990–995.
Ballatore C, Lee VM, Trojanowski JQ. Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci 2007; 8: 663–672.
Zhu XC, Yu JT, Jiang T, Tan L. Autophagy modulation for Alzheimer’s disease therapy. Mol Neurobiol 2013; 48: 702–714.
Klionsky DJ. Autophagy: from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol 2007; 8: 931–937.
Petiot A, Pattingre S, Arico S, Meley D, Codogno P. Diversity of signaling controls of macroautophagy in mammalian cells. Cell Struct Funct 2002; 27: 431–441. 8. Mizushima N, Levine B, Cuervo AM, Klionsky DJ. Autophagy fights disease through cellular self-digestion. Nature 2008; 451: 1069–1075.
Gordon PB, Seglen PO. Prelysosomal convergence of autophagic and endocytic pathways. Biochem Biophys Res Commun 1988; 151: 40–47.
Cuervo AM, Macian F. Autophagy and the immune function in aging. Curr Opin Immunol 2014; 29C: 97–104.
Yang Z, Klionsky DJ. Mammalian autophagy: core molecular machinery and signaling regulation. Curr Opin Cell Biol 2010; 22: 124–131.
Hamasaki M, Shibutani ST, Yoshimori T. Up-to-date membrane biogenesis in the autophagosome formation. Curr Opin Cell Biol 2013; 25: 455–460.
Sakai Y, Koller A, Rangell LK, Keller GA, Subramani S. Peroxisome degradation by microautophagy in Pichia pastoris: identification of specific steps and morphological intermediates. J Cell Biol 1998; 141: 625–636.
Sahu R, Kaushik S, Clement CC, Cannizzo ES, Scharf B, Follenzi A, Potolicchio I, Nieves E, Cuervo AM, Santambrogio L. Microautophagy of cytosolic proteins by late endosomes. Dev Cell 2011; 20: 131–139.
Kaushik S, Cuervo AM. Chaperone-mediated autophagy: a unique way to enter the lysosome world. Trends Cell Biol 2012; 22: 407–417.
Meijer AJ, Codogno P. Signalling and autophagy regulation in health, aging and disease. Mol Aspects Med 2006; 27: 411–425.
Yu L, McPhee CK, Zheng L, Mardones GA, Rong Y, Peng J, Mi N, Zhao Y, Liu Z, Wan F et al. Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature 2010; 465: 942–946.
Nobukuni T, Kozma SC, Thomas G. hvps34, an ancient player, enters a growing game: mTOR Complex1/S6K1 signaling. Curr Opin Cell Biol 2007; 19: 135–141.
Yu L, Alva A, Su H, Dutt P, Freundt E, Welsh S, Baehrecke EH, Lenardo MJ. Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 2004; 304: 1500– 1502.
Pickford F, Masliah E, Britschgi M, Lucin K, Narasimhan R, Jaeger PA, Small S, Spencer B, Rockenstein E, Levine B et al. The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J Clin Invest 2008; 118: 2190–2199.
Xie Z, Klionsky DJ. Autophagosome formation: core machinery and adaptations. Nat Cell Biol 2007; 9: 1102–1109.
Ling D, Salvaterra PM. A central role for autophagy in Alzheimer-type neurodegeneration. Autophagy 2009; 5: 738– 740.
Larsen KE, Sulzer D. Autophagy in neurons: a review. Histol Histopathol 2002; 17: 897–908.
Banerjee R, Beal MF, Thomas B. Autophagy in neurodegenerative disorders: pathogenic roles and therapeutic implications. Trends Neurosci 2010; 33: 541–549.
Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio AR, Healy DG et al. Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 2004; 304: 1158–1160.
Morimoto N, Nagai M, Ohta Y, Miyazaki K, Kurata T, Morimoto M, Murakami T, Takehisa Y, Ikeda Y, Kamiya T et al. Increased autophagy in transgenic mice with a G93A mutant SOD1 gene. Brain Res 2007; 1167: 112–117.
Munch C, Sedlmeier R, Meyer T, Homberg V, Sperfeld AD, Kurt A, Prudlo J, Peraus G, Hanemann CO, Stumm G et al. Point mutations of the p150 subunit of dynactin (DCTN1) gene in ALS. Neurology 2004; 63: 724–726.
Webb JL, Ravikumar B, Atkins J, Skepper JN, Rubinsztein DC. α-Synuclein is degraded by both autophagy and the proteasome. J Biol Chem 2003; 278: 25009–25013.
Banerjee R, Starkov AA, Beal MF, Thomas B. Mitochondrial dysfunction in the limelight of Parkinson’s disease pathogenesis. Biochim Biophys Acta 2009; 1792: 651–663.
Chu CT. A pivotal role for PINK1 and autophagy in mitochondrial quality control: implications for Parkinson disease. Hum Mol Genet 2010; 19: R28–37.
Dagda RK, Cherra SJ 3rd, Kulich SM, Tandon A, Park D, Chu CT. Loss of PINK1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission. J Biol Chem 2009; 284: 13843–13855.
Orr HT, Zoghbi HY. Trinucleotide repeat disorders. Annu Rev Neurosci 2007; 30: 575–621.
Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, Scaravilli F, Easton DF, Duden R, O’Kane CJ et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 2004; 36: 585–595.
Li L, Zhang X, Le W. Altered macroautophagy in the spinal cord of SOD1 mutant mice. Autophagy 2008; 4: 290–293.
Crippa V, Sau D, Rusmini P, Boncoraglio A, Onesto E, Bolzoni E, Galbiati M, Fontana E, Marino M, Carra S et al. The small heat shock protein B8 (HspB8) promotes autophagic removal of misfolded proteins involved in amyotrophic lateral sclerosis (ALS). Hum Mol Genet 2010; 19: 3440–3456.
Bateman RJ, Munsell LY, Morris JC, Swarm R, Yarasheski KE, Holtzman DM. Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo. Nat Med 2006; 12: 856–861.
Nixon RA. Autophagy, amyloidogenesis and Alzheimer disease. J Cell Sci 2007; 120: 4081–4091.
Yu WH, Cuervo AM, Kumar A, Peterhoff CM, Schmidt SD, Lee JH, Mohan PS, Mercken M, Farmery MR, Tjernberg LO et al. Macroautophagy--a novel beta-amyloid peptide-generating pathway activated in Alzheimer’s disease. J Cell Biol 2005; 171: 87–98.
Wolfe DM, Lee JH, Kumar A, Lee S, Orenstein SJ, Nixon RA. Autophagy failure in Alzheimer’s disease and the role of defective lysosomal acidification. Eur J Neurosci 2013; 37: 1949–1961.
Li W, Tang Y, Fan Z, Meng Y, Yang G, Luo J, Ke ZJ. Autophagy is involved in oligodendroglial precursor-mediated clearance of amyloid peptide. Mol Neurodegener 2013; 8: 27.
Fant X, Durieu E, Chicanne G, Payrastre B, Sbrissa D, Shisheva A, Limanton E, Carreaux F, Bazureau JP, Meijer L. cdc-like/ dual-specificity tyrosine phosphorylation-regulated kinases inhibitor leucettine L41 induces mTOR-dependent autophagy: implication for Alzheimer’s disease. Mol Pharmacol 2014; 85: 441–450.
François A, Terro F, Janet T, Rioux Bilan A, Paccalin M, Page G. Involvement of interleukin-1beta in the autophagic process of microglia: relevance to Alzheimer’s disease. J Neuroinflammation 2013; 10: 151.
Zhu Z, Yan J, Jiang W, Yao XG, Chen J, Chen L, Li C, Hu L, Jiang H, Shen X. Arctigenin effectively ameliorates memory impairment in Alzheimer’s disease model mice targeting both beta-amyloid production and clearance. J Neurosci 2013; 33: 13138–13149.
Caccamo A, Magri A, Medina DX, Wisely EV, Lopez-Aranda MF, Silva AJ, Oddo S. mTOR regulates tau phosphorylation and degradation: implications for Alzheimer’s disease and other tauopathies. Aging Cell 2013; 12: 370–380.
Xue Z, Zhang S, Huang L, He Y, Fang R, Fang Y. Upexpression of Beclin-1-dependent autophagy protects against beta- amyloid-induced cell injury in PC12 cells. J Mol Neurosci 2013; 51: 180–186.
Steele JW, Gandy S. Latrepirdine (Dimebon®), a potential Alzheimer therapeutic, regulates autophagy and neuropathology in an Alzheimer mouse model. Autophagy 2013; 9: 617–618.
Nixon RA, Wegiel J, Kumar A, Yu WH, Peterhoff C, Cataldo A, Cuervo AM. Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J Neuropathol Exp Neurol 2005; 64: 113–122.