Pyroglutamate–amyloid-β peptide expression in Drosophila leads to caspase-dependent and endoplasmic reticulum stress–related progressive neurodegeneration

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disorder among the elderly. During the progression of AD, massive neuronal degeneration occurs in the late stage of the disease; however, the molecular mechanisms responsible for this neuronal loss remain unknown. Aβ_pE3–42 (an N-terminal–truncated amyloid-β peptide that begins with pyroglutamate at the third position) is produced during late-stage AD. It also aggregates more rapidly in vitro and exhibits greater toxicity in neurons than full-length Aβ_1–42. In the present study, we established a Drosophila melanogaster model that expresses Aβ_3–42^E3Q, which effectively produces Aβ_pE3–42, and investigated the function of Aβ_pE3–42 using the photoreceptor neurons of Drosophila. Aβ_pE3–42 induced caspase-dependent apoptosis and caused progressive degeneration in photoreceptor neurons. Mutations in ER stress response genes or the administration of an inhibitor of the ER stress response markedly suppressed the degeneration phenotype, suggesting that the ER stress response plays an important role in neurodegeneration caused by Aβ_pE3–42. We also confirmed that human Tau-dependent apoptotic induction was strongly enhanced by Aβ_pE3–42. Thus, Aβ_pE3–42 expression system in the fly may be a promising new tool for studying late-onset neurodegeneration in AD.

from # All Medicine by Alexandros G. Sfakianakis via alkiviadis.1961 on Inoreader http://ift.tt/2hMNmrk