A Longitudinal Study of Cognition, Proton MR Spectroscopy and Synaptic and Neuronal Pathology in Aging Wild-type and AβPPswe-PS1dE9 Mice

Abstract

Proton magnetic resonance spectroscopy (1H MRS) is a valuable tool in Alzheimer’s disease research, investigating the functional integrity of the brainThe present longitudinal study set out to characterize the neurochemical profile of the hippocampus, measured by single voxel 1H MRS at 7 Tesla, in the brains of AβPPSswe-PS1dE9 and wild-type mice at 8 and 12 months of age. Furthermore, we wanted to determine whether alterations in hippocampal metabolite levels coincided with behavioral changes, cognitive decline and neuropathological features, to gain a better understanding of the underlying neurodegenerative processes. Moreover, correlation analyses were performed in the 12-month-old AβPP-PS1 animals with the hippocampal amyloid-β deposition, TBS-T soluble Aβ levels and high-molecular weight Aβ aggregate levels to gain a better understanding of the possible involvement of Aβ in neurochemical and behavioral changes, cognitive decline and neuropathological features in AβPP-PS1 transgenic mice. Our results show that at 8 months of age AβPPswe-PS1dE9 mice display behavioral and cognitive changes compared to age-matched wild-type mice, as determined in the open field and the (reverse) Morris water maze. However, there were no variations in hippocampal metabolite levels at this age. AβPP-PS1 mice at 12 months of age display more severe behavioral and cognitive impairment, which coincided with alterations in hippocampal metabolite levels that suggest reduced neuronal integrity. Furthermore, correlation analyses suggest a possible role of Aβ in inflammatory processes, synaptic dysfunction and impaired neurogenesis.

Effects of Specific Multi-Nutrient Enriched Diets on Cerebral Metabolism, Cognition and Neuropathology in AβPPswe-PS1dE9 Mice

“…In agreement with previous results from our lab [58], [76], 11-month-old AβPP-PS1 mice displayed increased activity and anxiety-related behavior, and decreased explorative behavior in the open field as compared to age-matched wild-type mice. Hyperactivity and decreased explorative behavior are specific characteristics of many AβPP transgenic mice [77]–[79] and may be explained as a result of elevated anxiety levels [80], [81].…”

“…In line with our previous findings [76], AβPP-PS1 and wild-type mice showed a similar decrease in escape latency during training in the reversal MWM. The reversal task requires selective memory retrieval of the newly learned location of the platform, and contains therefore an extra episodic component [60], [103].…”

“…In line with our previous results [58], [76], 11-month-old AβPP-PS1 mice also showed impaired performance in the MWM and rMWM as compared to age-matched wild-type animals. Although both AβPP-PS1 and wild-type mice showed a similar decrease in escape latency during training in the MWM, overall escape latencies were significantly higher in AβPP-PS1 mice, independent of dietary intake.…”

Brain Biomarkers in Familial Alzheimer’s Disease Mouse Models

“…Both FAD mice had the same metabolite profile in the DG as their wild type controls. A previous study investigating APPswe/PS1 ΔE9 mice by 1 H-MRS also found no variations in hippocampal metabolite levels at 8 months of age [24]. 3xTg-AD mice had elevated mI, glutamate, and glutamine in the cortex and no alterations in the SVZ.…”

In-vivoandin-vitrotechniques used to investigate Alzheimer's disease

“…myo-Inositol is a sugar alcohol that is thought to be a marker for osmotic stress, astrogliosis and microglial activation (Govindaraju et al 2000), and an increase in cerebral myo-inositol levels is therefore associated with inflammatory processes. Significant differences in hippocampal myo-inositol/glycine concentrations between 12-month-old wild-type and AβPP-PS1 mice were not observed, but correlation analysis revealed a positive correlation between the levels of Aβ-40 and Aβ-42 aggregates and myo-inositol/glycine levels in the AβPP-PS1 animals, suggesting the possible involvement of Aβ in the inflammatory process (Jansen et al 2013). Furthermore, disturbances of several other metabolites have been found in AD patients, although the reports are inconsistent.…”