Homer-1a immediate early gene expression correlates with better cognitive performance in aging

Abstract

The molecular mechanisms underlying cognitive decline during healthy aging remain largely unknown. Utilizing aged wild-type C57BL/6 mice as a model for normal aging, we tested the hypothesis that cognitive performance, memory, and learning as assessed in established behavioral testing paradigms are correlated with the differential expression of isoforms of the Homer family of synaptic scaffolding proteins. Here we describe a loss of cognitive and motor function that occurs when Homer-1a/Vesl-1S protein levels drop during aging. Our data describe a novel mechanism of age-related synaptic changes contributing to loss of biological function, spatial learning, and memory formation as well as motor coordination, with the dominant negative uncoupler of synaptic protein clustering, Homer-1a/Vesl-1S, as a potential target for the prophylaxis and treatment of age-related cognitive decline.

Differential Expression of Homer1a in the Hippocampus and Cortex Likely Plays a Role in Radiation-Induced Brain Injury

“…3A) and its downstream effectors at 2 months after fWBI (Fig. 3E), similar to that reported in mouse models of aging (49). …”

“…In a rat model of aging, increased expression of Homer1a and decreased mGluR5 signaling in the hippocampus were associated with cognitive deficits (61). Conversely, decreased Homer1a expression in the whole brain (largely cortical expression) was also associated with a loss of cognitive and motor function in mice (49). These data demonstrate that, depending on the brain region involved, both increased and decreased Homer1a expression can lead to cognitive impairment.…”

Caspase-3-Dependent Proteolytic Cleavage of Tau Causes Neurofibrillary Tangles and Results in Cognitive Impairment During Normal Aging

“…The behavioral outcome measures were described by us previously (Kaja et al 2013). Spatial learning and memory were determined using a swim maze test as described by us previously (Sumien et al 2006).…”

“…Total protein concentration was determined using the method of Lowry. Twenty-five micrograms of total protein in SDS loading buffer were separated electrophoretically and transferred to nitrocellulose membrane as described previously (Kaja et al 2013). Protein level quantification was performed by densitometry using ImageJ software (NIH).…”

“…In this study we used an established non-genetic preclinical model for aging (Kaja et al 2013; 2015) and showed that in cognitively impaired mice, cleaved tau, active caspases and NFTs were present and this correlated significantly to behavioral deficits. To our knowledge this is the first report of a non-transgenic, non-interventional mouse model displaying structural, functional and molecular aging deficits associated with AD and other tauopathies in humans.…”