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Neurotherapeutics. 2015 Jan;12(1):94-108. doi: 10.1007/s13311-014-0320-z.

Promoting autophagic clearance: viable therapeutic targets in Alzheimer's disease.

Author information

1
Department of Pathology and Cell Biology, Taub Institute for Alzheimer's Disease Research, Columbia University, 630 West 168th St., New York, NY, 10032, USA.

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 mTOR-independent 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.

PMID:
25421002
PMCID:
PMC4322072
DOI:
10.1007/s13311-014-0320-z
[Indexed for MEDLINE]
Free PMC Article

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