Abstract
Amyloid pathology occurs early in Alzheimer’s disease (AD), and has therefore been the focus of numerous studies. Transgenic mouse models have been instrumental to study amyloidosis, but observations might have been confounded by APP-overexpression artifacts. The current study investigated early functional defects in an APP knock-in mouse model, which allows assessing the effects of pathological amyloid-beta (Aβ) without interference of APP-artifacts. Female APPNL/NL knock-in mice of 3 and 7 months old were compared to age-matched APPNL-F/NL-F mice with increased Aβ42/40 ratio and initial Aβ-plaque deposition around 6 months of age. Spatial learning was examined using a Morris water maze protocol consisting of acquisition and reversal trials interleaved with reference memory tests. Functional connectivity (FC) of brain networks was assessed using resting-state functional MRI (rsfMRI). The Morris water maze data revealed that 3 months old APPNL-F/NL-F mice were unable to reach the same reference memory proficiency as APPNL/NL mice after reversal training. This cognitive defect in 3-month-old APPNL-F/NL-F mice coincided with hypersynchronous FC of the hippocampal, cingulate, caudate-putamen, and default-mode-like networks. The occurrence of these defects in APPNL-F/NL-F mice demonstrates that cognitive flexibility and synchronicity of telencephalic activity are specifically altered by early Aβ pathology without changes in APP neurochemistry.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disorder, characterized by progressive impairments in learning and memory, and other cognitive dysfunctions[1]
At 3 months of age (Fig. 1), repeated measures (RM) twoway ANOVA showed no statistical difference between the learning curves of APPNL-F/NL-F and APPNL/NL mice during acquisition (RM-ANOVA, ‘genotype x time’ interaction F9,135 = 0.446, p = 0.907, genotype effect F1,15 = 0.094, p = 0.763) or reversal trials (RM-ANOVA, ‘genotype x time’ interaction F 4,60 = 1.399, p = 0.245, genotype effect F1,15 = 1.244*10−5, p = 0.997)
RM-ANOVA indicated that all animals learnt the location of the platform during acquisition and reversal learning
Summary
Alzheimer’s disease (AD) is a neurodegenerative disorder, characterized by progressive impairments in learning and memory, and other cognitive dysfunctions[1]. Recent studies suggest that early disease signs are not caused by Aβ plaque deposition as such, but rather by pre-plaque levels of soluble Aβ peptides with high Aβ42/40 ratio[3,4,5]. High Aβ42/40 ratio prior to plaque deposition has been suggested to cause synaptic and neural network dysfunction leading to cognitive defects in early phases of AD3–5. We compared APPNL-F/NL-F knock-in mice with high Aβ42/40 ratio to APPNL/NL mice at two time points that reflect early pathological stages, i.e. before and at the initial stage of plaque deposition[8]. Previous studies have demonstrated the usefulness of rsfMRI to assess the functionality of brain networks in AD-related pharmacological models and transgenic mouse models[13,14,15,16]
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