β-Amyloid and Endoplasmic Reticulum Stress Reponses in Primary Neurons: Effects of Drugs That Interact With the Cytoskeleton

Abstract

In vitro studies designed to probe the cellular mechanisms underlying beta-amyloid (Abeta) toxicity in neurons have implicated several processes, including hyperphosphorylation of the microtubule (MT)-associated protein tau, loss of MT stability, and increased cytosolic calcium levels. Given that Alzheimer's disease involves accumulation of aggregates of two different proteins, the potential involvement of the unfolded protein response (UPR) and endoplasmic reticulum (ER) dysfunction has been suggested to lead to cell death. The relationship between these apparently divergent factors and pathways in Abeta toxicity is still unclear. In these studies we investigated the relationship between MT stability and the ER stress response in primary neurons exposed to toxic Abeta peptides in culture. In addition, nocodazole (ND) was used to determine if direct disruption of MT organization activated the UPR. Pretreatment of neurons with MT-stabilizing drugs paclitaxel (Taxol) and epothilone A prevented the induction of three indicators of the UPR induced by Abeta, ND, and thapsigargin, a compound known to inhibit the sarco-ER Ca(2+)-ATPase and deplete ER calcium stores, resulting in initiation of the UPR. In addition, treatment with MT-stabilizing drugs blocked cell death and the cytoskeletal disorganization induced by these insults. The results suggest that loss of cytoskeletal integrity is a very early step in the response to a variety of toxic stimuli and that preservation of MT stability might be important in preventing the induction of ER dysfunction and subsequent cell death by Abeta in neurons.

Induction of the unfolded protein response and cell death pathway in Alzheimer's disease, but not in aged Tg2576 mice

“…Amyloid β has been proposed as a potential trigger of ER stress in AD based upon the findings that the UPR and cell death pathway are induced in cultured neurons exposed to amyloid β or over-expressing mutant PS1 (Yu et al, 1999;Nakagawa et al, 2000;Ferreiro et al, 2006;Seyb et al, 2006). However, none of ER stress markers have been detected in the cortex of aged Tg2576 mice undergoing extensive amyloid β burden and cognitive deterioration.…”

Endoplasmic reticulum dysfunction in neurological disease

“…Moreover, exogenous A has been found to increase the phosphorylation of PERK and eIF2 in cultured neuronal cells 73,74 , while silencing of PERK by siRNA in A 42 .…”

“…Moreover, exogenous A has been found to increase the phosphorylation of PERK and eIF2 in cultured neuronal cells 73,74 , while silencing of PERK by siRNA in A 42 -treated cells limits eIF2 phosphorylation and enhances cell death 73 . In addition, A 42 treatment induces CHOP expression both in cultured cells and in rabbit hippocampus 75,76 , while prior treatment of cells with CHOP anti-sense RNA improves survival following exposure to the A peptide, suggesting a role for CHOP in A-mediated death 77 .…”

Role of p53 in Neurodegenerative Diseases

“…Several factors are thought to trigger neurodegeneration in AD, including cytoplasmic accumulation of ␤ -amyloid proteins [119,120] that may be responsible for inducing endoplasmic reticulum stress and cytoplasmic accumulation of phosphorylated Tau proteins that oligomerize to disrupt the cytoskeletal network [121,122] . Further, the vast majority of familiar AD cases consist of mutated presenilin-1 and/or presenilin-2 [123] .…”