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bioRxiv · 10.1101/2023.05.09.539973

Systematic characterization of a non-transgenic Amyloid-beta1-42 amyloidosis model: synaptic plasticity and memory deficits in female and male mice

Jimenez-Herrera, R.·Contreras, A.·Jeremic, D.·Iborra-Lazaro, G.·Djebari, S.·Navarro-Lopez, J. D.·Jimenez-Diaz, L. D.
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Abstract

BackgroundOne of the neuropathological hallmarks of Alzheimers disease (AD) is amyloid-{beta} (A{beta}) accumulation in the hippocampus that causes its dysfunction. This disruption includes excitatory/inhibitory imbalance, synaptic plasticity and oscillatory activity impairments, and memory deficits. Although AD prevalence is higher in women than men, the possible sex difference is scarcely explored and information from amyloidosis transgenic mice models is contradictory. Thus, given the lack of data of the early amyloidosis stages in females, the aim of this study was to systematically characterize the effect of an intracerebroventricular (icv.) injection of A{beta}1-42 on hippocampal-dependent memory, and on associated activity-dependent synaptic plasticity in the hippocampal CA1-CA3 synapse, in both male and female mice. MethodsTo do so, we evaluated long term potentiation (LTP) with ex vivo electrophysiological recordings and spatial (working, short- and long-term) and exploratory habituation memory using Barnes maze or open field habituation tasks respectively. ResultsWe found that A{beta}1-42 administration impairs all forms of memory evaluated, regardless the sex, in a long-lasting manner (up to 17 days post-injection). Furthermore, LTP was inhibited at a postsynaptic level, both in males and females, and a long-term depression (LTD) was induced for the same prolonged period, which could underly memory deficits. ConclusionsIn conclusion, our results provide further evidence of the shifting of LTP/LTD threshold due to a single icv. A{beta}1-42 injection, which underly cognitive deficits in early stages of AD. These long-lasting cognitive and functional alterations in males and females validate this model for the study of early amyloidosis in both sexes, thus offering a solid alternative to the inconsistence of amyloidosis transgenic mice models.

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Jimenez-Herrera, R., Contreras, A., Jeremic, D., Iborra-Lazaro, G., Djebari, S., Navarro-Lopez, J. D., Jimenez-Diaz, L. D.. 2023-05-09. Systematic characterization of a non-transgenic Amyloid-beta1-42 amyloidosis model: synaptic plasticity and memory deficits in female and male mice. https://doi.org/10.1101/2023.05.09.539973

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