Abstract
Autophagy has been reported to play a dual "double-edged sword" role in the occurrence and development of Alzheimer’s disease (AD). To assess the relationship between AD and autophagy, the dynamic changes of autophagic flux in the brain of postmortem AD patients, animal models and cell models were studied. The results showed that autophagosomes (APs) accumulation and expression of lysosomal markers were decreased in the brains of AD patients. In the brain of APP/PS1 double transgenic mice, APs did not accumulate before the formation of SPs but accumulated along with the deposition of SPs, as well as the level of lysosomal markers cathepsin B and Lamp1 protein decreased significantly. In the brains of APP/PS1/LC3 triple - transgenic mice, the number of APs increased with age, but the number of ALs did not increase accordingly. The activation of autophagy is mainly due to the increase in Aβ rather than the overexpression of mutated APP gene. However, both the treatment with exogenous Aβ25-35 and the mutation of the endogenous APP gene blocked the fusion of APs with lysosomes and decreased lysosomal functioning in AD model cells, which may be the main mechanism of autophagy dysregulation in AD.
Highlights
Alzheimer’s disease (AD), the main cause of dementia in the elderly, is a complex neurodegenerative disorder [1, 2]
Double immunofluorescence staining showed that the co-expression of the autophagy marker LC3 and the lysosomal marker Lamp1 was lower in AD patients than the controls, indicating the block in the fusion of APs and lysosomes, or the reduction in the number of lysosomes. (Figure 1H)
To study the role of autophagy in the pathogenesis of AD, the process of autophagic flux needs to be monitored dynamically, which is an important approach to reveal the pathogenesis of AD
Summary
Alzheimer’s disease (AD), the main cause of dementia in the elderly, is a complex neurodegenerative disorder [1, 2]. Mature APs are transported back to the cell body through the axonal microtubule system, fuse with lysosomes which mainly located around the nucleus to form autolysosomes (ALs) with monolayer membranes, and autophagy-related encapsulated proteins are released as a result of cathepsin (CTS) B and CTSD degradation. In their degradation, lysosomal acidification plays an important role [13]. It has been reported that autophagy acts as a "double-edged sword" in the development of AD [27,28,29,30,31,32,33,34,35]
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