Abstract
Alzheimer’s disease (AD) is the most common form of dementia in the elderly. According to the amyloid hypothesis, the accumulation and deposition of amyloid-beta (Aβ) peptides play a key role in AD. Soluble Aβ (sAβ) oligomers were shown to be 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 sAβ effects on functional resting-state networks in transgenic mature-onset amyloidosis Tet-Off APP (TG) mice. TG mice and control littermates were raised on doxycycline (DOX) diet from 3d up to 3 m of age to suppress transgenic Aβ production. Thereafter, longitudinal resting-state functional MRI was performed on a 9.4 T MR-system starting from week 0 (3 m old mice) up to 28w post DOX treatment. Ex-vivo immunohistochemistry and ELISA analysis was performed to assess the development of amyloid pathology. Functional Connectivity (FC) analysis demonstrated early abnormal hypersynchronisation in the TG mice compared to the controls at 8w post DOX treatment, 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 sAβ levels preceding the apparition of Aβ plaques and inflammatory responses 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 Aβ plaques in the brain. By preventing developmental influence of APP and/or sAβ during brain postnatal development, we demonstrated FC abnormalities potentially driven by sAβ neurotoxicity 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.
Highlights
Alzheimer’s disease (AD) is a devastating progressive neurodegenerative disorder, mainly characterized by the accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs), which leads to dementia [40]
The bigenic (TG) mice presented an alteration of functional connectivity (FC) over time Independent component analysis (ICA) that was performed across the population revealed 11 anatomically relevant neuronal components in the cortex and subcortical regions which were further clustered into larger functional networks such as the default mode network (DMN), sensory and subcortical networks (Additional file 1: Figure S1)
This study aimed to address the effects of soluble Aβ (sAβ) on the neuronal networks in mature-onset amyloidosis TG mice
Summary
Alzheimer’s disease (AD) is a devastating progressive neurodegenerative disorder, mainly characterized by the accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs), which leads to dementia [40]. Most of AD patients develop the late-onset sporadic form of AD (sAD), while the early-onset familial form of AD (fAD) is Evidence from studies on fAD (caused by genetic mutations) supported the idea, referred as “the amyloid hypothesis”, that the abnormal accumulation of extracellular soluble Aβ (sAβ) peptides is initiating AD pathology [30, 31]. Under pathological conditions and upon ageing, a metabolic dysregulation seems to cause the accumulation of sAβ peptides in the extracellular space, which oligomerize and aggregate, forming insoluble Aβ plaques [16, 57]. It is believed that sAβ oligomers are more synaptotoxic than the plaques, altering synaptic transmission and causing synapse loss and neuronal death [12, 32, 35], mainly in the cerebral cortex and certain subcortical regions [2], resulting in a progressive loss of cognitive functions [16]
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