Autophagy Modulation in Aggresome Formation: Emerging Implications and Treatments of Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is one of the most prevailing neurodegenerative diseases in the world, which is characterized by memory dysfunction and the formation of tau and amyloid β (Aβ) aggregates in multiple brain regions, including the hippocampus and cortex. The formation of senile plaques involving tau hyperphosphorylation, fibrillar Aβ, and neurofibrillary tangles (NFTs) is used as a pathological marker of AD and eventually produces aggregation or misfolded protein. Importantly, it has been found that the failure to degrade these aggregate-prone proteins leads to pathological consequences, such as synaptic impairment, cytotoxicity, neuronal atrophy, and memory deficits associated with AD. Recently, increasing evidence has suggested that the autophagy pathway plays a role as a central cellular protection system to prevent the toxicity induced by aggregation or misfolded proteins. Moreover, it has also been revealed that AD-related protein aggresomes could be selectively degraded by autophagosome and lysosomal fusion through the autophagy pathway, which is known as aggrephagy. Therefore, the regulation of autophagy serve as a useful approach to modulate the formation of aggresomes associated with AD. This review focuses on the recent improvements in the application of natural compounds and small molecules as a potential therapeutic approach for AD prevention and treatment via aggrephagy.

The Emerging Role of Autophagy as a Target of Environmental Pollutants: An Update on Mechanisms

“…Through its interaction with a scaffold protein, the receptor either binds to cargoes or may be an integral component of these cargoes, connecting them to the autophagy machinery in the cell [ 31 ]. Protein aggregates are associated with Alzheimer’s, Parkinson’s, and Huntington’s diseases [ 2 , 32 ]. In yeasts, flies, and mammalians, cells mediate amyloid beta peptide, tau, poly-Q, alpha-synuclein, and mutant huntingtin protein aggregates which might be removed by aggrephagy, a selective disposal of protein aggregates [ 2 , 33 ].…”

“…Protein aggregates are associated with Alzheimer’s, Parkinson’s, and Huntington’s diseases [ 2 , 32 ]. In yeasts, flies, and mammalians, cells mediate amyloid beta peptide, tau, poly-Q, alpha-synuclein, and mutant huntingtin protein aggregates which might be removed by aggrephagy, a selective disposal of protein aggregates [ 2 , 33 ]. Therefore, understanding the impacts of environmental pollutants on autophagy offers new ways for risk assessment, protection, and preventive actions to offset the harmful effects of environmental contaminants on human health.…”

“…Autophagy is an active component of cell defense and helps cancer cells maintain their cytostatic link during the growth process. [ 2 ]. Phagophore assembly sites (PAS), which are structures that come before autophagosomes, are initiated by autophagy process.…”

Therapeutic Aspects and Molecular Targets of Autophagy to Control Pancreatic Cancer Management

“…These actions cause the phagophore to enlarge and close, controlling the formation of the autophagosome [ 32 ]. The autophagosome’s two layers merge with lysosomes just before closing, permitting degradation of the inner membrane and intra-autophagosome transfer to begin [ 33 ].…”

“…While the majority of current attempts are directed at impairing autophagy in PC, the question of whether to restrict or stimulate autophagy remains. Autophagy activation using rapamycin-analog-mediated mTOR inhibition has highlighted an approach for investigating the use of PDAC models in clinical trials via inhibition of the PI3K/AKT signaling pathway [ 33 , 124 ]. However, while these results have not been interpreted as single agents, they show clinically important behavior in humans.…”