P3-399: Low molecular weight β-amyloid peptides induce endoplasmic reticulum aggregation in primary hippocampal neurons

Neuronal loss via different modes of neurodegeneration is a key issue 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. The endoplasmic reticulum (ER) plays significant roles in maintaining normal neuronal functions such as posttranslational modification of newly synthesized proteins. The wide-spread network of the ER is regulated by cytoskeleton. We hypothesize that β-amyloid (Aβ) peptide modulate cytoskeleton proteins affecting the integrity of the ER. Consequently, functions of the ER are impaired and synapses do not have newly synthesized proteins from the cell body. The aim of the study is to investigate whether extracellular Aβ peptide (1–42 & 1–40) how it will affect integrity of the ER. In this study, we employed primary cultures of hippocampal neurons. We used multiphoton microscopy to examine the ER. Also, we used immunocytochemical analysis to stain cytoskeleton proteins. Our previous publication has demonstrated that extracellular Aβ peptide can trigger release of Ca2+ from the ER without inducing unfolded-protein responses. Further investigation using live-cell imaging technology elucidates that ER aggregated in neurons after challenge by Aβ peptide. Loss of ER-retention protein, calreticulin, was also found in postmortem AD brain tissue. Aggregation of neurons was partly mediated via instability of tubulin. As a result of ER aggregation, there were increased numbers and size of lysosomes in neurons. Taken together, we provide evidence here to propose a new mechanism showing that lack of UPR because of the collapse/aggregation of the ER plays a role in Aβ peptide-triggered neurodegenerative process.