PERK mediates eIF2α phosphorylation responsible for BACE1 elevation, CREB dysfunction and neurodegeneration in a mouse model of Alzheimer's disease

NEUROBIOLOGY OF AGING

卷:35

Article

Devi, Latha¹  Ohno, Masuo^1,2 

[1] Ctr Dementia Res, Nathan Kline Inst, Orangeburg, NY 10962 USA

[2] NYU, Langone Med Ctr, Dept Psychiat, New York, NY 10016 USA

关键词: PERK;    eIF2 alpha;    BACE1;    Amyloid-beta;    ATF4;    CREB;    Cholinergic neuron;    Fear conditioning;    Learning and memory;    5XFAD;   

DOI  :  10.1016/j.neurobiolaging.2014.04.031

来源: Elsevier

【 摘 要 】

Emerging evidence suggests that aberrant phosphorylation of eukaryotic initiation factor-2 alpha (eIF2 alpha) may induce synaptic failure and neurodegeneration through persistent translational inhibition of global protein synthesis. However, elevated phospho-eIF2 alpha also paradoxically causes translational activation of a subset of messenger RNAs such as the beta-secretase enzyme, beta-site APP-cleaving enzyme 1 (BACE1) and cAMP response element binding protein (CREB) repressor, activating transcription factor 4 (ATF4). Therefore, we tested whether genetic reduction of the eIF2 alpha kinase PERK may prevent these deleterious events and mitigate Alzheimer's disease (AD)-like neuropathology and cognitive impairments in the 5XFAD mouse model. PERK haploinsufficiency blocked overactivation of the PERK-eIF2 alpha pathway, as evidenced by significant reductions in phosphorylation of PERK and eIF2 alpha, in 5XFAD mice. PERK haploinsufficiency was sufficient to rescue memory deficits and cholinergic neurodegeneration in this AD model. Notably, PERK haploinsufficiency also prevented BACE1 elevations, resulting in reduced levels of amyloid-beta peptides and plaque burden in 5XFAD mice. Moreover, CREB dysfunction was restored in PERK+/-.5XFAD mice concomitant with reversal of ATF4 upregulation. Together, these findings suggest that PERK may be a disease-modifying therapeutic target to prevent multiple memory-disrupting mechanisms associated with AD. (C) 2014 Elsevier Inc. All rights reserved.

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