Alzheimer's disease-related misfolded proteins and dysfunctional organelles on autophagy menu

• Published in: DNA and cell biology Vol. 34; no. 4; p. 261
• Main Authors: Correia, Sónia C, Resende, Rosa, Moreira, Paula I, Pereira, Cláudia M
• Format: Journal Article
• Language: English
• Published: United States 01.04.2015
• Subjects: Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Animals; Autophagy; Endoplasmic Reticulum Stress; Humans; Mitochondria - metabolism; Mitochondria - pathology; Protein Folding
• ISSN: 1557-7430
• DOI: 10.1089/dna.2014.2757

Autophagy is a housekeeping process responsible for the bulk degradation of misfolded protein aggregates and damaged organelles through the lysosomal machinery. Given its key role as a cellular quality control mechanism, autophagy is now a focus of intense scrutiny in Alzheimer's disease (AD). The hallmarks of this devastating neurodegenerative disease are the accumulation of misfolded amyloid-β (Aβ) peptide and hyperphosphorylated tau protein and neuronal loss, which are accompanied by mitochondrial dysfunction and endoplasmic reticulum (ER) stress, suggesting that faulty autophagy is a contributing factor to AD pathology. Indeed, the AD brain is characterized by a massive accumulation of autophagic vacuoles within large swellings along dystrophic neurites and defects at different steps of the autophagic-lysosomal pathway. In this sense, this review provides an overview on the role of autophagy on Aβ metabolism, tau processing and clearance, and the contribution of ER-phagy and mitophagy to AD pathology. From a therapeutic perspective, this review also intends to clarify whether, when, and how autophagy can be targeted to efficaciously counteract AD-related symptomatic and neuropathological features.