Low molecular weight Aβ peptide leads to endoplasmic reticulum aggregation by interfering the microtubule stability

Abstract

Different modes of neurodegeneration contribute to the neuronal cell death in Alzheimer’s disease (AD). Increasing lines of evidence have demonstrated that synaptic degeneration and dysfunction of axonal transport may be the initial degenerative processes in AD. Endoplasmic reticulum (ER) is an important organelle that responsible for Ca2+ homeostasis, protein folding, post-translational modification, protein degradation, and transportation of nascent protein. Here we aim to examine the impact of sublethal dose of low molecular weight Aβ on the ER morphology. Low molecular weight of Aβ induces collapse of ER and affects anchoring the ER to microtubule (MT). In addition, the acetylation level of tubulin that related to the stability of microtubule is also decreased. Furthermore, prolonged treatment of low molecular weight Aβ triggers autophagy and enhances lysosome degradation. Loss of ER-retention protein, calreticulin, is also found in postmortem AD brain tissue. Treatment of MT-stabilizing agent, Taxol and histone deactylase inhibitor, trichostatin A can inhibit collapse of the ER. The results provide evidence to show that Aβ-induced disruption of MT can affect not only axonal transport but also intracellular organelles architecture such as the ER. Taken together, we provide evidence here to propose a new mechanism showing that collapse/aggregation of the ER plays a role in Aβ peptide-triggered neurodegenerative process.