Role of Endoplasmic Reticulum Stress in Learning and Memory Impairment and Alzheimer's Disease-Like Neuropathology in the PS19 and APP Swe Mouse Models of Tauopathy and Amyloidosis

Abstract Emerging evidence suggests that endoplasmic reticulum (ER) stress may be involved in the pathogenesis of Alzheimer9s disease (AD). Recently, pharmacological modulation of the Eukaryotic Initiation Factor 2-alpha (eIF2α) pathway was achieved using an Integrated Stress Response Inhibitor (ISRIB). While members of this signaling cascade have been suggested as potential therapeutic targets for neurodegeneration, the biological significance of this pathway has not been comprehensively assessed in animal models of AD. The present study investigated the ER stress pathway and its long-term modulation utilizing in vitro and in vivo experimental models of tauopathy (MAPT P301S)PS19 and amyloidosis (APP Swe ). We report that thapsigargin induces activating transcription factor 4 (ATF4) in primary cortical neurons (PCNs) derived from rat and APP Swe non-transgenic and transgenic mice. ISRIB mitigated the induction of ATF4 in PCNs generated from wild-type but not APP Swe mice despite partially restoring thapsigargin-induced translational repression in non-transgenic PCNs. In vivo , C57BL/6J and PS19 mice received prolonged, once-daily administration of ISRIB. While the compound was well tolerated by PS19 and C57BL/6J mice, APP Swe mice treated per this schedule displayed significant mortality. Thus, the dose was reduced and administered only on behavioral test days. ISRIB did not improve learning and memory function in APP Swe transgenic mice. While ISRIB did not reduce tau-related neuropathology in PS19 transgenic mice, no evidence of ER stress-related dysfunction was observed in either of these transgenic models. Taken together, the significance of ER stress and the relevance of these models to the etiology of AD require further investigation. Significance Statement Accumulating evidence suggests that endoplasmic reticulum (ER) stress is involved in cellular processes relevant to neuronal survival and death in disorders of the CNS. We assessed the ER stress pathway and the effects of its modulation using in vitro and in vivo experimental models of tauopathy and excessive amyloidosis. Use of an Integrated Stress Response Inhibitor (ISRIB) was not effective at improving the behavioral impairments and neuropathology observed in these models. While no evidence of ER stress or ER stress-related dysfunction involving ATF4 and CHOP was found in these transgenic mice, ISRIB partially restored thapsigargin-induced translational repression in vitro in primary mouse cortical neurons. In summary, the contribution of ER stress to the etiology of AD warrants further investigation.