beta-Amyloid and endoplasmic reticulum stress responses in primary neurons: effects of drugs that interact with the cytoskeleton.
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.
Seyb
Kathleen I
KI
Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS 66045, USA.
Ansar
Sabah
S
Bean
Jennifer
J
Michaelis
Mary L
ML