UsingDrosophilaModels of Amyloid Toxicity to Study Autophagy in the Pathogenesis of Alzheimer’s Disease

Abstract

Autophagy is a conserved catabolic pathway that involves the engulfment of cytoplasmic components such as large protein aggregates and organelles that are delivered to the lysosome for degradation. This process is important in maintaining neuronal function and raises the possibility of a role for autophagy in neurodegenerative diseases. Alzheimer's disease (AD) is the most prevalent form of these diseases and is characterized by the accumulation of amyloid plaques in the brain which arise due to the misfolding and aggregation of toxic peptides, including amyloid beta (Aβ). There is substantial evidence from both AD patients and animal models that autophagy is dysregulated in this disease. However, it remains to be determined whether this is protective or pathogenic as there is evidence that autophagy can act to promote the degradation as well as function in the generation of toxic Aβ peptides. Understanding the molecular details of the extensive crosstalk that occurs between the autophagic and endolysosomal cellular pathways is essential for identifying the molecular details of amyloid toxicity. Drosophila models that express the toxic proteins that aggregate in AD have been generated and have been shown to recapitulate hallmarks of the disease. Here we focus on what is known about the role of autophagy in amyloid toxicity in AD from mammalian models and how Drosophila models can be used to further investigate AD pathogenesis.

An updated analysis of the association between CD2-associated protein gene rs9349407 polymorphism and Alzheimer’s disease in Chinese population

“…These results suggest that CD2AP neuronal expression is associated with 3R-tau-disease ( Camacho et al, 2022 ). Additionally, various studies have suggested that CD2AP is involved in autophagy signaling, the blood-brain barrier, as well as regulating neurite length, neurite complexity, and growth cone filopodia in neurons ( Harrison et al, 2016 ; O’Keefe and Denton, 2018 ; Sweeney et al, 2018 ).…”

The role of CD2AP in the Pathogenesis of Alzheimer's Disease

“…No obviously other behavioral abnormalities were observed [56]. CD2AP and several other AD risk genes (BIN1 and PICALM) were also predicated to participate in autophagy pathway [57,58]. In CD2AP −/− podocytes, one of the important proteins in autophagy signaling (p62) was upregulated, indicating the absence of CD2AP induced podocyte injury by affecting autophagy signaling.…”

Loss of Hsp67Bc leads to autolysosome enlargement in the Drosophila brain

“…As a well-studied multicellular organism, the fruit fly D. melanogaster can be used as a model to investigate autophagy in the context of development, aging, and various stressors (McPhee & Baehrecke, 2009). The fruit fly is a popular model animal for investigating the role of macroautophagy in protein aggregation disorders (Khan et al, 2020;Kinghorn et al, 2016;O'Keefe & Denton, 2018). The involvement of macroautophagy in an innate immune response has been shown for the symbiotic association of D. melanogaster with Wolbachia bacteria (Deehan et al, 2021;Voronin et al, 2012).…”