Accession Number:

AD1095588

Title:

The Impact of PERK on Post-Traumatic Tauopathy in Alzheimers Disease

Descriptive Note:

Technical Report,15 Sep 2017,14 Sep 2018

Corporate Author:

University of Kentucky Lexington United States

Personal Author(s):

Report Date:

2018-10-01

Pagination or Media Count:

28.0

Abstract:

Risk for AD is one of the most imminent threats to military personnel sustaining TBI. A major challenge in the field of TBIAD research is elucidation of the molecular mechanisms linking TBI with tau pathogenesis that is associated with AD. This critical and urgently needed information will identify novel therapeutic targets that will benefit both military personnel and civilian population. Our data indicate that TBI induces sustained and dramatic endoplasmic reticulum stress, and that there is a pathological relationship between AD tau species and the ER stress sensor PERK. In this proposal, we aimed to establish the impact of PERK on TBI outcomes and whether or not manipulating PERK alters tau-mediated pathogenesis following injury. Here, we aimed to directly address the role of PERK activity as a molecular mediator of TBI-induced sequelae and provide unique understanding of the association between TBI and tau. To date, our data outline a time-course of PERK activation following TBI and indicate sustained PERK activity in neurons for as long as 30 days. Chemical inhibition of PERK for 30 days following TBI resulted in successful knockdown of the PERK pathway and inflammatory markers, as well as a trending reduction in PERK-related apoptotic signaling protein CHOP. TBI in a conditional knockout mice lacking neuronal PERK demonstrated less conclusive results as global levels of PERK in the brain were unchanged, suggesting an upregulation of glial PERK after injury. Continued work will assess changes in pathological tau species in these mouse models following TBI to specifically assess the effects of PERK modulation on tau protein following TBI.

Subject Categories:

  • Anatomy and Physiology
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE