METAPLASTICITY IN A MOUSE MODEL OF ALZHEIMER’S DISEASE AND POSSIBLE THERAPEUTIC INTERVENTIONS

Alzheimer"s disease;metaplasticity;not listed

Megill, Andrea LaurenWong, Philip C ;

Johns Hopkins University

关键词: Alzheimer";    s disease;    metaplasticity;    not listed;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/60315/MEGILL-DISSERTATION-2014.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, causing loss of synaptic contacts and cognitive decline. It is widely believed that AD is initiated by synaptic dysfunction caused by production of Aβ peptides. Therefore, understanding how the progression of amyloidogenesis alters synaptic function is imperative in developing effective therapeutics for disease intervention.While many studies have focused on how Aβ peptides and the progression of AD affect frequency-dependent long-term potentiation and long-term depression (LTP/LTD), it is unclear whether synaptic dysfunction is at the level of induction or expression of synaptic plasticity mechanisms. Here we report that there is an age-dependent alteration in synaptic plasticity at the Schaffer collateral inputs to CA1 of APPswe;PS1deltaE9 AD transgenic (Tg) mice. Young pre-amyloidogenic Tgs showed enhanced LTP at the expense of LTD, while adult post-amyloidogenic Tgs showed enhanced LTD at the expense of LTP. The apparent shift in plasticity was mediated by altered LTP/LTD expression mechanisms, and in particular due to an absence of a normal age-dependent shift in pull-push metaplasticity. These results suggest that the main synaptic deficit in AD Tg mice is due to their inability to developmentally regulate LTP/LTD expression in accord with the pull-push metaplasticity model. Current AD therapeutics provide only temporary symptomatic relief, but need to strive to mitigate the long term progression of the disease by targeting the specific cellular mechanisms that become disrupted. Recognizing that cognitive decline during AD is correlated with loss of dendritic spine density, we examined two novel therapies that increase dendritic spine density through a Ras/ERK dependent mechanism. We found that the increase in dendritic spine density was better correlated with cognitive performance than the absolute magnitude of LTP. While these therapies were investigated in wild type mice, they both exhibit potential as drug candidates for AD treatment and warrant further studies to determine their effects in mouse models of AD.In summary, this project provides a novel mechanistic viewpoint in understanding the synaptic dysfunction seen in AD that can lead to the development of more effective therapeutics by specifically targeting the fundamental cellular mechanisms that are disrupted, such as pull-push metaplasticity.