Hippocampal dysregulation of synaptic plasticity-associated proteins with age-related cognitive decline

Abstract

Age-related cognitive decline occurs without frank neurodegeneration and is the most common cause of memory impairment in aging individuals. With increasing longevity, cognitive deficits, especially in hippocampus-dependent memory processes, are increasing in prevalence. Nevertheless, the neurobiological basis of age-related cognitive decline remains unknown. While concerted efforts have led to the identification of neurobiological changes with aging, few age-related alterations have been definitively correlated to behavioral measures of cognitive decline. In this work, adult (12 Months) and aged (28 months) rats were categorized by Morris water maze performance as Adult cognitively Intact, Aged cognitively Intact or Aged cognitively Impaired, and protein expression was examined in hippocampal synaptosome preparations. Previously described differences in synaptic expression of neurotransmission-associated proteins (Dnm1, Hpca, Stx1, Syn1, Syn2, Syp, SNAP25, VAMP2 and 14-3-3 eta, gamma, and zeta) were confirmed between Adult and Aged rats, with no further dysregulation associated with cognitive impairment. Proteins related to synaptic structural stability (MAP2, drebrin, Nogo-A) and activity-dependent signaling (PSD-95, 14-3-3θ, CaMKIIα) were up- and down-regulated, respectively, with cognitive impairment but were not altered with increasing age. Localization of MAP2, PSD-95, and CaMKIIα demonstrated protein expression alterations throughout the hippocampus. The altered expression of activity- and structural stability-associated proteins suggests that impaired synaptic plasticity is a distinct phenomenon that occurs with age-related cognitive decline, and demonstrates that cognitive decline is not simply an exacerbation of the aging phenotype.

Inflammatory insult during pregnancy accelerates age-related behavioral and neurobiochemical changes in CD-1 mice

“…Moreover, our data also showed that the increased Syt-1 and decreased Stx-1 were associated with decreased ability in terms of spatial learning and memory in the RAWM. These results were in line with previous reports (Chen et al 2007b;Tong et al 2015;VanGuilder et al 2011). As hypothesized, the LPS treatment dose-dependently accelerated the changes of Syt-1 and Stx-1 in the hippocampus of the older CD-1 mice, suggesting that exposure to LPS during pregnancy could accelerate the age-related changes of Syt-1 and Stx-1.…”

“…Our previous and other studies have shown that the hippocampal level of Syt-1 increases with aging and is associated with AAMI in senescence-accelerated prone mice P8 (SAMP8) (Chen et al 2007b;Tong et al 2015), whereas Stx-1 levels decrease in normal-aged rodents VanGuilder et al 2011) and transgenic AD mice (Wirths and Bayer 2010). So, Aβ 42 , p-tau, Syt-1, and Stx-1 can be regarded as age-related neurobiochemical indicators linked to AAMI.…”

Higher levels of phosphorylated Y1472 on GluN2B subunits in the frontal cortex of aged mice are associated with good spatial reference memory, but not cognitive flexibility

“…Another study subdivided aged rats into impaired and intact groups based on cognitive status and examined PSD-95 expression in the hippocampus. The authors found that performance in probe trials for spatial memory retention correlated positively with PSD-95 expression in the aged rats (VanGuilder et al 2011). Conversely, in a similar experimental design, reference memory acquisition was negatively correlated with PSD-95 in the hippocampus of rats in all age groups (Nyffeler et al 2007).…”

Dysregulation of 14‐3‐3 proteins in neurodegenerative diseases with Lewy body or Alzheimer pathology

“…14‐3‐3 proteins are highly expressed throughout the brain, with high levels associated with neurons, but expression is also detected in glial cells and endothelial cells 32, 33, 34, 35, 36, 37. We performed immunohistochemistry on free‐floating sections from control brains and brains with both AD and PD pathology to determine which cell populations expressed 14‐3‐3s and S232 phosphorylation.…”

“…High levels of 14‐3‐3s are primarily expressed in neurons, but expression of 14‐3‐3s is detectable in non‐neuronal populations, including glial and endothelial cells 32, 33, 34, 35, 36, 37. As our western blot analysis cannot distinguish whether 14‐3‐3s were associated with neurons or other non‐neuronal cells, we performed immunohistochemistry for 14‐3‐3s on sections from control brains and brains with both AD and PD pathology.…”