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

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, ATG7, BCL2, BECN1, CDK5, CLU, CTSD, FOXO1, GFAP, ITPR1, MAPT, PSEN1, SNCA, UBQLN1, and UCHL1. 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.

PI3K activation prevents Aβ42-induced synapse loss and favors insoluble amyloid deposits formation

“…S2). This result is in line with others, where mTOR is found to participate in memory formation and consolidation, and seems targeted by Aβ42 (Lin et al, 2014;Mueed et al, 2019;Uddin et al, 2018). Thus, mTOR inhibition may be another experimental strategy, independent from PI3K activation, to be considered in future AD studies.…”

Enrichment of rare protein truncating variants in amyotrophic lateral sclerosis patients

“…Aberrant protein aggregation due to misfolding or accumulation of degraded proteins, is one of the pathological hallmarks of neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, Huntington's disease, prion disease, and ALS (Brundin et al, 2010;Imarisio et al, 2008;Irwin et al, 2013;Ross and Poirier, 2004;Uddin et al, 2018;Winklhofer et al, 2008). HSP proteins have a conserved and central role in protein function by aiding in their folding and stabilization, and the clearance of misfolded proteins, ultimately diminishing protein aggregates and the associated pathologies.…”

Exosome release and cargo in Down syndrome

“…Enhanced exosome secretion is thought to be a compensatory mechanism in response to cellular stressors. Recent molecular studies suggest that specific molecular checkpoints, such as ATG5, ATG7, and CD63, interface with the control of exosomal release (Abdulrahman, Abdelaziz, & Schatzl, 2018;Uddin et al, 2018). Tetraspanins, a family of transmembrane proteins (e.g., CD63 and CD81) are among the most abundant surface proteins on exosomes (Booth et al, 2006;Raposo & Stoorvogel, 2013) and are often used to quantify total exosome secretion.…”

“…It was also shown that significantly more GSLs in exosomes from neurons than in those from glial cells (Yuyama & Igarashi, 2017). Since the autophagosome and other degradation pathways are disrupted in both AD and DS (Colacurcio et al, 2018;Nixon, 2017;Tramutola et al, 2016;Uddin et al, 2018), Aβ may accumulate and propagate by disrupting the normal degradation of amyloid peptides. Collective evidence strongly suggests that this is an early event, prior to the accumulation of other pathological hallmarks (Nixon, 2017).…”