Abstract
Advanced age and mutations in the genes encoding amyloid precursor protein (APP) and presenilin (PS1) are two serious risk factors for Alzheimer's disease (AD). Finding common pathogenic changes originating from these risks may lead to a new therapeutic strategy. We observed a decline in memory performance and reduction in hippocampal long-term potentiation (LTP) in both mature adult (9–15 months) transgenic APP/PS1 mice and old (19–25 months) non-transgenic (nonTg) mice. By contrast, in the presence of bicuculline, a GABAA receptor antagonist, LTP in adult APP/PS1 mice and old nonTg mice was larger than that in adult nonTg mice. The increased LTP levels in bicuculline-treated slices suggested that GABAA receptor-mediated inhibition in adult APP/PS1 and old nonTg mice was upregulated. Assuming that enhanced inhibition of LTP mediates memory decline in APP/PS1 mice, we rescued memory deficits in adult APP/PS1 mice by treating them with another GABAA receptor antagonist, picrotoxin (PTX), at a non-epileptic dose for 10 days. Among the saline vehicle-treated groups, substantially higher levels of synaptic proteins such as GABAA receptor α1 subunit, PSD95, and NR2B were observed in APP/PS1 mice than in nonTg control mice. This difference was insignificant among PTX-treated groups, suggesting that memory decline in APP/PS1 mice may result from changes in synaptic protein levels through homeostatic mechanisms. Several independent studies reported previously in aged rodents both an increased level of GABAA receptor α1 subunit and improvement of cognitive functions by long term GABAA receptor antagonist treatment. Therefore, reduced LTP linked to enhanced GABAA receptor-mediated inhibition may be triggered by aging and may be accelerated by familial AD-linked gene products like Aβ and mutant PS1, leading to cognitive decline that is pharmacologically treatable at least at this stage of disease progression in mice.
Highlights
Both aging and mutations in genes that encode amyloid precursor protein (APP) and presenilin (PS) are considered to be major risk factors for Alzheimer’s disease (AD)
On the basis of changes we observed in memory performance and long-term potentiation (LTP) linked with enhanced GABAA receptor-mediated inhibition, we tested the effects of picrotoxin (PTX), a GABAA receptor antagonist and observed that 10 days of PTX treatment improves the cognitive functions of adult APP/PS1 mice
A direct comparison showed a significant difference between adult nonTg and adult APP/PS1 mice (**p = 0.0033; two-tailed Mann-Whitney U test), indicating that the memory of adult APP/PS1 mice was less accurate, since higher probe scores mean that a mouse was swimming in an area distant from the target
Summary
Both aging and mutations in genes that encode amyloid precursor protein (APP) and presenilin (PS) are considered to be major risk factors for Alzheimer’s disease (AD). Cognitive abilities decline with age, yet a recognizable subpopulation of older individuals maintains mental abilities [5]. Both aging and gene risks are known to be tightly associated with glutamate excitotoxicity via calcium dysregulation [6,7,8]. The complex symptoms of AD and their partial correlation with pathological hallmarks indicate that understanding the pathogenesis of AD may require investigations of abnormalities at multiple levels; this would enhance our awareness that various compensatory mechanisms are at work in maintaining brain functions [9]. On the basis of changes we observed in memory performance and LTP linked with enhanced GABAA receptor-mediated inhibition, we tested the effects of picrotoxin (PTX), a GABAA receptor antagonist and observed that 10 days of PTX treatment improves the cognitive functions of adult APP/PS1 mice
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