EARLY STRUCTURAL AND BEHAVIOURAL DIFFERENCES IN APPSWE/PS1ΔE9 MOUSE MODEL OF ALZHEIMER’S DISEASE

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by decline in cognitive functions, including memory impairment. We examined structural changes in neuronal morphology in CA1 region of the hippocampus in APPSwe/PS1ΔE9 (APP/PS1) mice. We further evaluated these structural changes with hippocampal dependent learning tasks. Golgi staining - Brains from 1 month old APP/PS1 mice (wild-type and transgenic) were fixed for Golgi staining and 100 μm serial sections were cut for spine and morphometric analyses. Novel-object recognition (NOR), Object-place recognition (OPR), Object-in-context recognition (OCR) were used to study different aspects of episodic memory. For analysis, the test phase in all the three tasks were converted into a discrimination ratio. The Morris water maze (MWM) - The mouse is trained to navigate a pool with opaque water and find the hidden platform. The reversal phase started on day 6, at which point the platform was moved to the opposite quadrant of the tank. Results at the probe trial represented spatial memory. Contextual fear conditioning (cFC) – It involves pairing of a conditioned stimulus with an aversive unconditioned stimulus (footshock). As a result of these pairings, animals freeze to the neutral stimulus such as the training context (CS) upon subsequent presentations. Apical dendritic spine loss, including reduction in mushroom spine density is seen as early as 1 month of age in CA1 region of the hippocampus of APP/PS1 mice. Significant deficits were observed upon hippocampal dependent episodic-like memory task requiring the binding of an object memory into a spatial context such as OCR and OPR. No difference was seen in NOR, which unlike the other components of episodic-like memory is considered not to critically rely on the hippocampus. In MWM, mice showed no difference in acquisition but had less preference for the target quadrant compared to the wildtype upon reversal learning. APP/PS1 mice also showed contextual fear learning deficits. Our study demonstrates that AD-relevant pathological changes affecting structural and behavioral features start early and progress with increasing age in APP/PS1 mice.