Pharmacological modulation of autophagy for Alzheimer's disease therapy: Opportunities and obstacles

Abstract

Alzheimer's disease (AD) is a prevalent and deleterious neurodegenerative disorder characterized by an irreversible and progressive impairment of cognitive abilities as well as the formation of amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs) in the brain. By far, the precise mechanisms of AD are not fully understood and no interventions are available to effectively slow down progression of the disease. Autophagy is a conserved degradation pathway that is crucial to maintain cellular homeostasis by targeting damaged organelles, pathogens, and disease-prone protein aggregates to lysosome for degradation. Emerging evidence suggests dysfunctional autophagy clearance pathway as a potential cellular mechanism underlying the pathogenesis of AD in affected neurons. Here we summarize the current evidence for autophagy dysfunction in the pathophysiology of AD and discuss the role of autophagy in the regulation of AD-related protein degradation and neuroinflammation in neurons and glial cells. Finally, we review the autophagy modulators reported in the treatment of AD models and discuss the obstacles and opportunities for potential clinical application of the novel autophagy activators for AD therapy.

Keywords: Alzheimer's disease; Autophagy; Autophagy modulators; Genetic modulation; LC3-associated phagocytosis; Microglial autophagy; Neuroinflammation; Neuronal autophagy.

Graphical abstract

Figure 1

Autophagy process and dysfunction in AD. The autophagy process starts with the formation of an isolated membrane to sequester the protein aggregates and intracellular organelles to form a double membrane structure called phagophore. During elongation, phagophore expands to form autophagosome. Upon the autophagosome formation, it directly fuses with lysosome and endosome to generate autolysosome and endolysosome, respectively, to digest and recycle cargo. Pathogenic proteins including Aβ aggregates and hyperphosphorylated tau, as well as damaged organelles including mitochondria can be efficiently cleared by autophagy to maintain neuronal homeostasis. The autophagy proteins highlighted with red rectangular lines are those downregulated in AD models. The proteins with red color are AD-associated proteins impairing autophagy–lysosome/later endosome pathway in different steps.

Figure 2

Autophagy in neurons and microglia regulates AD pathology. In neurons, depletion of autophagy key proteins impairs neuronal autophagy and causes accumulation of Aβ species and neurofibrillary tangles, and eventual neurodegeneration in AD models, whereas overexpression of autophagy proteins reduces AD pathology by promoting the clearance of Aβ species and neurofibrillary tangles in AD models. In microglia, depletion of autophagy key proteins impairs neuronal autophagy of Aβ species and causes activation of NLRP3 inflammasome, release of pro-inflammasome cytokins (e.g., IL-1β), and eventual neuroinflammation. In addition, disruption of LAP/LANDO impairs the phagocytosis of Aβ species and causes neuroinflammation in AD models.

Figure 3

Analysis of research quality of chemical autophagy modulators. (A) The number of compounds belonging to autophagy inducers or inhibitors. (B) and (C) The number of studies completed in each category in Autophagy Modulator Scoring System (AMSS) -A and -B. (D) The list of autophagy modulators studies most cited. (E) The list of autophagy modulators reported at least twice.