Increased soluble amyloid-beta causes early aberrant brain network hypersynchronisation in a mature-onset mouse model of amyloidosis

Abstract

BackgroundAlzheimers disease (AD) is the most common form of dementia in the elderly population. Currently, no effective cure is available for AD. According to the amyloid hypothesis, the accumulation and deposition of the amyloid-beta (A{beta}) peptides plays a key role in AD pathology. Soluble A{beta} (sA{beta}) oligomers were shown to be synaptotoxic and involved in pathological hypersynchronisation of brain resting-state networks in different transgenic developmental-onset mouse models of amyloidosis. However, the impact of protein overexpression during brain postnatal development may cause additional phenotypes unrelated to AD. To address this concern, we investigated sA{beta} effects on functional resting-state networks in transgenic mature-onset amyloidosis Tet-Off APP (TG) mice.\n\nMethodsTG mice and control littermates were raised on doxycycline (DOX) diet from 3d up to 3m of age to suppress transgenic A{beta} production. Thereafter, longitudinal resting-state functional MRI was performed on a 9.4T MR-system starting from week 0 (3m old mice) up to 28w post DOX treatment. Ex vivo immunohistochemistry and ELISA analysis (additional mice cohort) was performed to address the development of amyloid pathology.\n\nResultsFunctional Connectivity (FC) analysis demonstrated early abnormal hypersynchronisation in the TG mice compared to the controls at 8w post DOX treatment. This effect was observed particularly across regions of the default mode-like network, known to be affected in AD. Ex vivo analyses performed at this time point confirmed a 20-fold increase in total sA{beta} levels and the absence of A{beta} plaques in the TG mice compared to the controls. On the contrary at week 28, TG mice showed an overall hypoconnectivity, coinciding with a widespread deposition of A{beta} plaques in the brain.\n\nConclusionsBy preventing developmental influence of APP and/or sA{beta} during brain postnatal development, we demonstrated FC abnormalities driven by sA{beta} synaptotoxicity on resting state neuronal networks in mature-induced TG mice. Thus, the Tet-Off APP mouse model could be a powerful tool while used as a mature-onset model to shed light into amyloidosis mechanisms in AD. Therefore, this inducible APP expression model used in combination with early non-invasive in vivo rsfMRI readout for sA{beta} synaptotoxicity sets the stage for future A{beta} targeting preventative treatment studies.