Autophagy and Alzheimer's Disease: From Molecular Mechanisms to Therapeutic Implications

Overview

Journal Front Aging Neurosci

Specialty Geriatrics

Date 2018 Feb 15

PMID 29441009

Citations 190

Authors

Md Sahab Uddin

Anna Stachowiak

Abdullah Al Mamun

Nikolay T Tzvetkov

Shinya Takeda

Atanas G Atanasov

Leandro B Bergantin

Mohamed M Abdel-Daim

Adrian M Stankiewicz

Affiliations

Soon will be listed here.

Abstract

Alzheimer's disease (AD) is the most common cause of progressive dementia in the elderly. It is characterized by a progressive and irreversible loss of cognitive abilities and formation of senile plaques, composed mainly of amyloid β (Aβ), and neurofibrillary tangles (NFTs), composed of tau protein, in the hippocampus and cortex of afflicted humans. In brains of AD patients the metabolism of Aβ is dysregulated, which leads to the accumulation and aggregation of Aβ. Metabolism of Aβ and tau proteins is crucially influenced by autophagy. Autophagy is a lysosome-dependent, homeostatic process, in which organelles and proteins are degraded and recycled into energy. Thus, dysfunction of autophagy is suggested to lead to the accretion of noxious proteins in the AD brain. In the present review, we describe the process of autophagy and its importance in AD. Additionally, we discuss mechanisms and genes linking autophagy and AD, i.e., the mTOR pathway, neuroinflammation, endocannabinoid system, , and . We also present pharmacological agents acting via modulation of autophagy that may show promise in AD therapy. This review updates our knowledge on autophagy mechanisms proposing novel therapeutic targets for the treatment of AD.

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References

Roberts H, Schneider B, Brown D . α-Synuclein increases β-amyloid secretion by promoting β-/γ-secretase processing of APP. PLoS One. 2017; 12(2):e0171925. PMC: 5302447. DOI: 10.1371/journal.pone.0171925. View

Xue Z, Zhang S, Huang L, He Y, Fang R, Fang Y . Increased expression of Beclin-1-dependent autophagy protects against beta-amyloid-induced cell injury in PC12 cells [corrected]. J Mol Neurosci. 2013; 51(1):180-6. DOI: 10.1007/s12031-013-9974-y. View

Choi J, Levey A, Weintraub S, Rees H, Gearing M, Chin L . Oxidative modifications and down-regulation of ubiquitin carboxyl-terminal hydrolase L1 associated with idiopathic Parkinson's and Alzheimer's diseases. J Biol Chem. 2004; 279(13):13256-64. DOI: 10.1074/jbc.M314124200. View

Okuma T, Kishimoto A . A history of investigation on the mood stabilizing effect of carbamazepine in Japan. Psychiatry Clin Neurosci. 1998; 52(1):3-12. DOI: 10.1111/j.1440-1819.1998.tb00966.x. View

Maroof N, Pardon M, Kendall D . Endocannabinoid signalling in Alzheimer's disease. Biochem Soc Trans. 2013; 41(6):1583-7. DOI: 10.1042/BST20130140. View

Oddo S, Caccamo A, Smith I, Green K, LaFerla F . A dynamic relationship between intracellular and extracellular pools of Abeta. Am J Pathol. 2006; 168(1):184-94. PMC: 1592652. DOI: 10.2353/ajpath.2006.050593. View

Larson M, Sherman M, Greimel S, Kuskowski M, Schneider J, Bennett D . Soluble α-synuclein is a novel modulator of Alzheimer's disease pathophysiology. J Neurosci. 2012; 32(30):10253-66. PMC: 3425439. DOI: 10.1523/JNEUROSCI.0581-12.2012. View

Gong B, Pan Y, Vempati P, Zhao W, Knable L, Ho L . Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-γ coactivator 1α regulated β-secretase 1 degradation and mitochondrial gene expression in Alzheimer's mouse models. Neurobiol Aging. 2013; 34(6):1581-8. PMC: 3632303. DOI: 10.1016/j.neurobiolaging.2012.12.005. View

Natunen T, Takalo M, Kemppainen S, Leskela S, Marttinen M, Kurkinen K . Relationship between ubiquilin-1 and BACE1 in human Alzheimer's disease and APdE9 transgenic mouse brain and cell-based models. Neurobiol Dis. 2015; 85:187-205. DOI: 10.1016/j.nbd.2015.11.005. View

10.

Ueda K, Fukushima H, Masliah E, Xia Y, Iwai A, Yoshimoto M . Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc Natl Acad Sci U S A. 1993; 90(23):11282-6. PMC: 47966. DOI: 10.1073/pnas.90.23.11282. View

11.

Oikawa T, Nonaka T, Terada M, Tamaoka A, Hisanaga S, Hasegawa M . α-Synuclein Fibrils Exhibit Gain of Toxic Function, Promoting Tau Aggregation and Inhibiting Microtubule Assembly. J Biol Chem. 2016; 291(29):15046-56. PMC: 4946922. DOI: 10.1074/jbc.M116.736355. View

12.

Yoshimoto M, Iwai A, Kang D, Otero D, Xia Y, Saitoh T . NACP, the precursor protein of the non-amyloid beta/A4 protein (A beta) component of Alzheimer disease amyloid, binds A beta and stimulates A beta aggregation. Proc Natl Acad Sci U S A. 1995; 92(20):9141-5. PMC: 40940. DOI: 10.1073/pnas.92.20.9141. View

13.

Singh M, Jensen M, Lerman A, Kushwaha S, Rihal C, Gersh B . Effect of Low-Dose Rapamycin on Senescence Markers and Physical Functioning in Older Adults with Coronary Artery Disease: Results of a Pilot Study. J Frailty Aging. 2016; 5(4):204-207. DOI: 10.14283/jfa.2016.112. View

14.

Sarkar S, Floto R, Berger Z, Imarisio S, Cordenier A, Pasco M . Lithium induces autophagy by inhibiting inositol monophosphatase. J Cell Biol. 2005; 170(7):1101-11. PMC: 2171537. DOI: 10.1083/jcb.200504035. View

15.

Martorell M, Forman K, Castro N, Capo X, Tejada S, Sureda A . Potential Therapeutic Effects of Oleuropein Aglycone in Alzheimer's Disease. Curr Pharm Biotechnol. 2016; 17(11):994-1001. DOI: 10.2174/1389201017666160725120656. View

16.

Colasanti T, Vomero M, Alessandri C, Barbati C, Maselli A, Camperio C . Role of alpha-synuclein in autophagy modulation of primary human T lymphocytes. Cell Death Dis. 2014; 5:e1265. PMC: 4047919. DOI: 10.1038/cddis.2014.211. View

17.

Rubinsztein D, Marino G, Kroemer G . Autophagy and aging. Cell. 2011; 146(5):682-95. DOI: 10.1016/j.cell.2011.07.030. View

18.

Dolan P, Johnson G . A caspase cleaved form of tau is preferentially degraded through the autophagy pathway. J Biol Chem. 2010; 285(29):21978-87. PMC: 2903354. DOI: 10.1074/jbc.M110.110940. View

19.

Cerpa W, Hancke J, Morazzoni P, Bombardelli E, Riva A, Marin P . The hyperforin derivative IDN5706 occludes spatial memory impairments and neuropathological changes in a double transgenic Alzheimer's mouse model. Curr Alzheimer Res. 2009; 7(2):126-33. DOI: 10.2174/156720510790691218. View

20.

Iijima K, Ando K, Takeda S, Satoh Y, Seki T, Itohara S . Neuron-specific phosphorylation of Alzheimer's beta-amyloid precursor protein by cyclin-dependent kinase 5. J Neurochem. 2000; 75(3):1085-91. DOI: 10.1046/j.1471-4159.2000.0751085.x. View