Promoting Autophagic Clearance: Viable Therapeutic Targets in Alzheimer's Disease

Abstract

Many neurodegenerative disorders are characterized by the aberrant accumulation of aggregate-prone proteins. Alzheimer's disease (AD) is associated with the buildup of β-amyloid peptides and tau, which aggregate into extracellular plaques and neurofibrillary tangles, respectively. Multiple studies have linked dysfunctional intracellular degradation mechanisms with AD pathogenesis. One such pathway is the autophagy-lysosomal system, which involves the delivery of large protein aggregates/inclusions and organelles to lysosomes through the formation, trafficking, and degradation of double-membrane structures known as autophagosomes. Converging data suggest that promoting autophagic degradation, either by inducing autophagosome formation or enhancing lysosomal digestion, provides viable therapeutic strategies. In this review, we discuss compounds that can augment autophagic clearance and may ameliorate disease-related pathology in cell and mouse models of AD. Canonical autophagy induction is associated with multiple signaling cascades; on the one hand, the best characterized is mammalian target of rapamycin (mTOR). Accordingly, multiple mTOR-dependent and mTORindependent drugs that stimulate autophagy have been tested in preclinical models. On the other hand, there is a growing list of drugs that can enhance the later stages of autophagic flux by stabilizing microtubule-mediated trafficking, promoting lysosomal fusion, or bolstering lysosomal enzyme function. Although altering the different stages of autophagy provides many potential targets for AD therapeutic interventions, it is important to consider how autophagy drugs might also disturb the delicate balance between autophagosome formation and lysosomal degradation.

Walking the tightrope: proteostasis and neurodegenerative disease

“…Misfolded proteins can be degraded by chaperone-mediated autophagy and autophagy activation appears to protect against a-synuclein-induced neurodegeneration (Xilouri et al 2013). This exciting observation represents part of a growing awareness that the autophagy/ lysosomal cascade may contain therapeutic targets for the treatment of neurodegenerative diseases (Friedman et al 2015). However, while there is great hope for the clinical management of neurodegenerative diseases via up-regulation of degradative pathways, many unknowns still need to be addressed before these pathways can be therapeutically targeted.…”

Targeting neuronal MAPK14/p38α activity to modulate autophagy in the Alzheimer disease brain

“…Interestingly, deficiency in PS1 (presenilin 1), mutations in which are the most common cause of familial AD, leads to lysosomal dysfunction 3,4,5 . Modulation of the autophagy-lysosomal pathway is therefore an interesting target for the treatment of neurodegenerative disease, 6,7 and proof of concept using genetic approaches has been obtained in different animal models. For example, in mouse models for AD amyloid pathology the phenotype can be rescued by increasing lysosomal degradation 8,9 .…”

Salacia chinensis L. Stem Extract Exerts Antifibrotic Effects on Human Hepatic Stellate Cells through the Inhibition of the TGF-β1-Induced SMAD2/3 Signaling Pathway

“…HSC migration has been identified as an initial process which causes hepatic tissue remodeling and fibrotic progression [25]. We identified the effect of SC stem extract on HSCs migration by observing its ability to inhibit the wound healing process.…”