Further investigation on biological mechanisms of endoplasmic reticulum aggregation and autophagy triggered by oligomeric beta-amyloid peptides in neurons

Abstract

Alzheimer’s Disease (AD) is an age-dependent neurodegenerative diseases presented with progressive memory loss and cognitive impairment. Amyloid plaque is one of the proteinopathy and pathological hallmark of the disease. The beta amyloid peptides inside this plaque contribute to neuronal stresses, and eventually lead to neuronal death. Autophagy is a well-known cellular mechanisms to salvage nutrient and energy, as well as to eliminate misfolded proteins and dysregulated organelles to tide over stressful crisis, and its enhancement is remarkably implicated in the disease progression. The goal of this study is to further investigate how the beta amyloid oligomers initiates autophagy and the nature of beta amyloid oligomers triggered autophagy. Using various imaging and biochemical methods in primary hippocampal neuronal cultures, I found that oligomeric Ab triggered autophagy may be initiated by aggregation and ubiquitination of the endoplasmic reticulum (ER), leading to the active recruitment of autophagic receptor p62, and thus LC3, and other regulators and machineries involved in autophagy. The mode of activation is different from classical autophagy where ULK1 is activated by upstream signalling. In oligomeric Ab triggered autophagy, neither AMPK nor mTOR is involved. By understanding more on how this type of autophagy works, we may be able to find a possible way of intervention on manipulating autophagy as a potential therapeutic strategy for AD patients.