Inhibition of Early Growth Response 1 in the Hippocampus Alleviates Neuropathology and Improves Cognition in an Alzheimer Model with Plaques and Tangles

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Abstract

A sporadic form of Alzheimer disease (AD) and vascular dementia share many risk factors, and their pathogenic mechanisms are suggested to be related. Transcription factor early growth response 1 (Egr-1) regulates various vascular pathologies and is up-regulated in both AD brains and AD mouse models; however, its role in AD pathogenesis is unclear. Herein, we report that silencing of Egr-1 in the hippocampus by shRNA reduces tau phosphorylation, lowers amyloid-β (Aβ) pathology, and improves cognition in the 3xTg-AD mouse model. Egr-1 silencing does not affect levels of cyclin-dependent protein kinase 5 (Cdk5), glycogen synthase kinase 3β, protein phosphatase 1, or protein phosphatase 2A, but reduces p35 subunit of Cdk5. Egr-1 silencing also reduces levels of β-secretase 1 (BACE-1) and BACE-1–cleaved amyloid precursor protein (APP) metabolites (secreted APPβ, C99, Aβ40, and Aβ42) but has no effect on presenilin 1 and presenilin 2. In hippocampal primary neurons, Egr-1 binds to BACE-1 and p35 promoters, enhances tau phosphorylation, activates Cdk5 and BACE-1, and accelerates amyloidogenic APP processing. Blocking Cdk5 action blocks Egr-1–induced tau phosphorylation but has no effect on BACE-1 activation and amyloidogenic APP processing. Blocking BACE-1 action, on the other hand, blocks Egr-1–induced amyloidogenic APP processing but does not affect tau phosphorylation. Egr-1 regulates tau phosphorylation and Aβ synthesis in the brain by respectively controlling activities of Cdk5 and BACE-1, suggesting that Egr-1 is a potential therapeutic candidate for the treatment of AD.

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Qin, X., Wang, Y., & Paudel, H. K. (2017). Inhibition of Early Growth Response 1 in the Hippocampus Alleviates Neuropathology and Improves Cognition in an Alzheimer Model with Plaques and Tangles. American Journal of Pathology, 187(8), 1828–1847. https://doi.org/10.1016/j.ajpath.2017.04.018

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