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

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.

Vulnerability and resilience to Alzheimer’s disease: early life conditions modulate neuropathology and determine cognitive reserve

“…More recently, EGR1 has also been implicated as a driving factor of AD neuropathology and cognitive decline, since hippocampal EGR1 inhibition was shown to reduce tau phosphorylation, lower Aβ pathology, and improve cognition in 3xTG-AD mice [ 183 ]. Since EGR1 inhibition was also shown to activate BACE1 activity [ 184 ], this calls for further studies into the role of (early life) modulation of EGR1 and its implication in cognitive impairment and AD neuropathology.…”

SNCA genetic lowering reveals differential cognitive function of alpha-synuclein dependent on sex

“…Subsequent studies reported Egr1 protein elevations in cognitively-impaired Tg2576, APP/PS1 and 3xTg-AD mouse models of AD [ 4 , 19 , 26 ]. Conversely, knockdown of EGR1 improved cognitive deficits in 3xTgAD mice [ 46 ]. Overall, these studies suggest that sustained elevated expression of EGR1 is detrimental for long-term memory.…”

Protein-protein interactions underlying the behavioral and psychological symptoms of dementia (BPSD) and Alzheimer’s disease

“…Specifically, these proteins are Low Density Lipoprotein Receptor-Related Protein 1 (LRP1), a cholesterol receptor that mediates endocytosis and binds to over 40 ligands [86], Epidermal Growth Factor Receptor (EGFR), a receptor tyrosine kinase in the neuregulin/ERBB family[87], 14-3-3beta (YWHAB), a phosphoserine/phosphotyrosine binding protein of the 14-3-3 family that interacts with a wide-range of other proteins to facilitate protein interactions [88], Small Ubiquitin Related Modifier 1 (SUMO1), a ubiquitin-like post-translational modification that affects a broad range of protein functions [89], and Early Growth Receptor 1 (EGR1), a transcription factor that represents an intermediate-early gene marking neuronal activation and synaptic plasticity [90]. All five of these proteins have been implicated in AD pathogenesis: LRP1 is a receptor that interacts with Abeta and APOE, which may influence LRP1's ability to aid in Abeta clearance [86]; EGFR polymorphisms were found to be inversely proportional to AD risk in a Han Chinese cohort [91]; 14-3-3 can be found around Abeta plaques and facilitates GSKbeta-mediated phosphorylation of tau [92]; SUMO1 expression is altered in cortices of AD patients [93]; and EGR1 inhibition leads to decreased Abeta and p-tau while reversing cognitive deficits in 3xTg AD mice [94]. However, the links between these proteins and HIDA Domain symptoms are sparse.…”