Autophagy: A double-edged sword in Alzheimer’s disease

Abstract

Autophagy is a major protein degradation pathway that is essential for stress-induced and constitutive protein turnover. Accumulated evidence has demonstrated that amyloid-beta (A beta) protein can be generated in autophagic vacuoles, promoting its extracellular deposition in neuritic plaques as the pathological hallmark of Alzheimer's disease (AD). The molecular machinery for A beta generation, including APP, APP-C99 and beta-/gamma-secretases, are all enriched in autophagic vacuoles. The induction of autophagy can be vividly observed in the brain at early stages of sporadic AD and in an AD transgenic mouse model. Accumulated evidence has also demonstrated a neuroprotective role of autophagy in mediating the degradation of aggregated proteins that are causative of various neurodegenerative diseases. Autophagy is thus widely regarded as an intracellular hub for the removal of the detrimental A beta peptides and Tau aggregates. Nonetheless, compelling data also reveal an unfavorable function of autophagy in facilitating the production of intracellular A beta. The two faces of autophagy on the homeostasis of A beta place it in a very unique and intriguing position in AD pathogenesis. This article briefly summarizes seminal discoveries that are shedding new light on the critical and unique roles of autophagy in AD and potential therapeutic approaches against autophagy-elicited AD.

Effect of Cholesterol Reduction on Receptor Signaling in Neurons

“…Autophagy is a lysosome-directed vesicular trafficking pathway and a major degradation pathway of intracellular components that is essential for survival and adaptation to nutrient elimination (37). Autophagy also plays a role in maintenance of neuronal cells and has been implicated in clearance of pathogens and antigen presentation (38), including the clearance of amyloid ␤ protein from neuronal cells (39). LC3I is converted to LC3II by lipidation during autophagy.…”

ErbB2 regulates autophagic flux to modulate the proteostasis of APP-CTFs in Alzheimer’s disease

“…Ras GTPase activation mediates EGF-induced stimulation of γ-secretase to increase the nuclear function of the APP intracellular domain (AICD) (11). Consistent with the role of EGF signaling in AD, the intracellular mediators downstream of EGF signaling (which include Grb2, ShcA, and Abl) directly or indirectly interact with APP (12); these findings support the correlation between EGFR/ ErbB-dependent signaling and AD susceptibility.Autophagy controls the clearance of misfolded proteins and damaged organelles, and plays an essential role in maintaining neuronal functions (13,14). Previous studies have demonstrated that autophagy is instrumental to the clearance of proteins related to neurodegenerative diseases; these proteins include polyglutamine aggregates in Huntington's disease, Lewy body-like α-synuclein aggregates in Parkinson's disease, and neurofibrillary tangles in AD (15-18).…”

“…Autophagy controls the clearance of misfolded proteins and damaged organelles, and plays an essential role in maintaining neuronal functions (13,14). Previous studies have demonstrated that autophagy is instrumental to the clearance of proteins related to neurodegenerative diseases; these proteins include polyglutamine aggregates in Huntington's disease, Lewy body-like α-synuclein aggregates in Parkinson's disease, and neurofibrillary tangles in AD (15)(16)(17)(18).…”

Overexpression of let-7a increases neurotoxicity in a PC12 cell model of Alzheimer's disease via regulating autophagy

“…Briefly, 2x10 6 cells from different groups were washed with PBS, stained with Annexin V-FITC and PI for 15 min in the dark at room temperature. Then samples (10,000 cells/sample) were analyzed using a flow cytometer (BD Accuri C6; BD Biosciences, San Jose, CA, USA).…”

“…Increasing evidence has suggested that autophagy is a double-edged sword in AD development (6). Although a great deal of research has demonstrated that autophagy has a beneficial effect against AD (7)(8)(9), abnormalities of autophagy may also be a major risk factor for AD (10).…”