Alzheimer's disease (AD) is a prevalent neurodegenerative disorder that affects memory and learning abilities. The disease is characterized by the presence of β-amyloid plaque and neurofibrillary tangles. In this article, the authors provide an update on the interactions between Alzheimer’s disease, autophagy, and inflammation.
The authors first discuss the burden of Alzheimer’s disease, which includes not only the cost of treatment but also loss of productivity and caregiver burden. They note that many neurodegenerative diseases are chronic and have disabling effects that continue for years or even decades. The overall burden of neurodegenerative diseases may be much greater than suggested, and Alzheimer’s disease is no exception. The American Alzheimer Association reported in 2018 that 5.4 million people have AD in the United States, and the cost of this disease for the US is $200 billion per year. By 2050, the Association estimates that the number will reach up to 11-16 million in the US.
The authors then provide an overview of the neuropathology of Alzheimer’s disease, which is characterized by severe impairments of memory, cognition, and motor functions. They note that there are two forms of this disease: sporadic and familial AD. The majority of the cases indicate sporadic forms, which are multifactorial and involve both genetic predisposition and environmental factors. In contrast, the familial form arises from the mutations of three genes: amyloid precursor protein (APP), presenilin 1 (PS 1), and presenilin 2 (PS 2).
The authors also discuss the pathogenesis of Alzheimer’s disease, which is characterized by accelerated depositions of extracellular amyloid peptides and neurofibrillary tangles in the soma. They note that Aβ peptides are produced from a type 1 transmembrane protein with 770 amino acids called amyloid precursor protein (APP). Aβ monomer released from the membrane changes its structures from α-helix to β-sheet by misfolding, which leads to the formation of semi-stabile, soluble, and short Aβ oligomers. The authors discuss the cascade of events that follow, called the “Amyloid Cascade Hypothesis,” which posits that oligomeric Aβ peptide (Aβ42) accumulation causes inflammation, synaptic degradation, mitochondrial dysfunction, ER stress, and oxidative damage in neurons and glia.
Furthermore, the authors provide an overview of autophagy and its role in the normal physiology processes, as well as in the pathogenesis of various diseases, including Alzheimer’s disease. Autophagy is a regulated process for the degradation of cytosolic cargo, including misfolded proteins and damaged organelles, to maintain cellular homeostasis. The authors note that autophagy has a critical role in neuronal homeostasis and that it may play a role in the pathogenesis of neurodegenerative diseases.
Finally, the authors examine the interaction between autophagy and inflammation and suggest possible treatment strategies. They note that impaired autophagic and inflammation flux can change the course of neurodegenerative diseases. Therefore, well-designed experimental studies investigating the interactions between autophagy and inflammation may be able to reveal new promising therapeutic approaches. The authors suggest that the clearance of tau protein may be clinically more important than Aβ clearance in AD. Indeed, the authors suggest that autophagy may play a critical role in the clearance of tau protein and that modulating autophagy may provide a potential therapeutic strategy for AD.
In sum, this article provides a comprehensive review of the current state of knowledge regarding Alzheimer’s disease and its interactions with autophagy and inflammation. The authors note that the burden of AD is significant, and there is still no effective treatment method. However, they suggest that modulating autophagy may provide a potential therapeutic strategy for AD, and they encourage further research in this area.
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