Autophagy Modulation as a Treatment of Amyloid Diseases

Abstract

Amyloids are fibrous proteins aggregated into toxic forms that are implicated in several chronic disorders. More than 30 diseases show deposition of fibrous amyloid proteins associated with cell loss and degeneration in the affected tissues. Evidence demonstrates that amyloid diseases result from protein aggregation or impaired amyloid clearance, but the connection between amyloid accumulation and tissue degeneration is not clear. Common examples of amyloid diseases are Alzheimer’s disease (AD), Parkinson’s disease (PD) and tauopathies, which are the most common forms of neurodegenerative diseases, as well as polyglutamine disorders and certain peripheral metabolic diseases. In these diseases, increased accumulation of toxic amyloid proteins is suspected to be one of the main causative factors in the disease pathogenesis. It is therefore important to more clearly understand how these toxic amyloid proteins accumulate as this will aide in the development of more effective preventive and therapeutic strategies. Protein homeostasis, or proteostasis, is maintained by multiple cellular pathways—including protein synthesis, quality control, and clearance—which are collectively responsible for preventing protein misfolding or aggregation. Modulating protein degradation is a very complex but attractive treatment strategy used to remove amyloid and improve cell survival. This review will focus on autophagy, an important clearance pathway of amyloid proteins, and strategies for using it as a potential therapeutic target for amyloid diseases. The physiological role of autophagy in cells, pathways for its modulation, its connection with apoptosis, cell models and caveats in developing autophagy as a treatment and as a biomarker is discussed.

PRKAG2 Gene Expression Is Elevated and its Protein Levels Are Associated with Increased Amyloid-β Accumulation in the Alzheimer’s Disease Brain

“…Our findings showing increased gene expression of PRKAG2, a positive regulator of autophagy suggest that it may be a contributing factor to autophagy induction in AD. The autophagy pathway is impaired at different steps in neurodegenerative diseases and mostly associated with increased autophagy initiation and reduced autophagosome degradation [1,15]. Our findings showing increased PRKAG2 gene expression in AD combined with a positive association with A␤ levels suggest that PRKAG2 dysfunction is specific to AD and related to A␤ accumulation, a pathological hallmark of AD.…”

The Bewildering Effect of AMPK Activators in Alzheimer’s Disease: Review of the Current Evidence

“…is impairment in autophagic flux may be secondary to either impairment in axonal trafficking or insufficient lysosome acidification [67,68]. Recent studies show that AMPK activation not only enhances autophagosome formation but also enhances autophagosome clearance.…”

Protein Homeostasis Networks and the Use of Yeast to Guide Interventions in Alzheimer’s Disease

“…AD is characterized by the accumulation of unwanted toxic protein aggregates including tau neurofibrillary tangles and Aβ aggregates (oligomers, fibrils, and senile plaques) [2]. From previous studies, it has been found that the protein quality control and the cellular defense system has failed severely during AD progression [348]. The impact of AD pathogenesis can be found at all the levels of the proteostasis network.…”