Activate or Inhibit? Implications of Autophagy Modulation as a Therapeutic Strategy for Alzheimer’s Disease

Abstract

Neurodegenerative diseases result in a range of conditions depending on the type of proteinopathy, genes affected or the location of the degeneration in the brain. Proteinopathies such as senile plaques and neurofibrillary tangles in the brain are prominent features of Alzheimer’s disease (AD). Autophagy is a highly regulated mechanism of eliminating dysfunctional organelles and proteins, and plays an important role in removing these pathogenic intracellular protein aggregates, not only in AD, but also in other neurodegenerative diseases. Activating autophagy is gaining interest as a potential therapeutic strategy for chronic diseases featuring protein aggregation and misfolding, including AD. Although autophagy activation is a promising intervention, over-activation of autophagy in neurodegenerative diseases that display impaired lysosomal clearance may accelerate pathology, suggesting that the success of any autophagy-based intervention is dependent on lysosomal clearance being functional. Additionally, the effects of autophagy activation may vary significantly depending on the physiological state of the cell, especially during proteotoxic stress and ageing. Growing evidence seems to favour a strategy of enhancing the efficacy of autophagy by preventing or reversing the impairments of the specific processes that are disrupted. Therefore, it is essential to understand the underlying causes of the autophagy defect in different neurodegenerative diseases to explore possible therapeutic approaches. This review will focus on the role of autophagy during stress and ageing, consequences that are linked to its activation and caveats in modulating this pathway as a treatment.

Alzheimer’s Disease Pathogenesis: Role of Autophagy and Mitophagy Focusing in Microglia

“…Autophagy (meaning “self-eating” in Greek) is one of the main pathways for the removal of damaged proteins and organelles. It works by carrying the protein aggregates and damaged organelles into lysosomes [ 53 , 54 , 55 , 56 ]. However, the function of autophagy in neurons is more than just simple housekeeping tasks and involves several neuronal specific functions such as axonal guidance, synaptic transmission, proper neuronal connectivity, and neural stem cell development [ 57 , 58 ].…”

Phytochemicals as a Complement to Cancer Chemotherapy: Pharmacological Modulation of the Autophagy-Apoptosis Pathway

“…Autophagy is a cellular process that breaks down or degrades unwanted or aggregated dysfunctional cellular components through fusion with lysosomes; this cellular process is known to play an essential role in maintaining cellular function as well as homeostasis (Krishnan et al, 2020). Autophagy preserves an active interlink in cell defense as well as a cytostatic link in cancer cell progression (Rahman and Rhim, 2017).…”

Autophagy and Tau Protein

“…Increased clearance of tau in AD mice [83,84] siRNA(calpain knockdown) Inhibit calpain activation [82] Optogenetic TFEB inducer TFEB induction [75] Although activation of autophagy is a promising therapeutic approach, over-activation of autophagy in neurodegenerative diseases where lysosomal clearance is impaired may promote pathogenesis. In other words, the success of autophagy-based therapy depends on lysosome clearance [85]. Furthermore, the effects of autophagy activation can vary greatly depending on the physiological status of the cell, especially in response to proteotoxic stress and aging.…”

“…Furthermore, the effects of autophagy activation can vary greatly depending on the physiological status of the cell, especially in response to proteotoxic stress and aging. In order to increase the effectiveness of autophagy, strategies to prevent or reverse the disruption of specific processes that have been disrupted are now considered to be important [ 85 ].…”

“…The function of autophagy in cell death and its detailed mechanisms remain unknown, and it is not clear whether autophagy-induced cell death is associated with apoptosis or whether it is a separate process [ 85 ].…”