Aging-Dependent Loss of Connectivity in Alzheimer’s Model Mice with Rescue by mGluR5 Modulator

Abstract

Amyloid accumulation in Alzheimer’s disease (AD) is associated with synaptic damage and altered connectivity in brain networks. While measures of amyloid accumulation and biochemical changes in mouse models have utility for translational studies of certain therapeutics, preclinical analysis of altered brain connectivity using clinically relevant fMRI measures has not been well developed for agents intended to improve neural networks. Here, we conduct a longitudinal study in a double knock-in mouse model for AD (AppNL-G-F/hMapt), monitoring brain connectivity by means of resting-state fMRI. While the 4-month-old AD mice are indistinguishable from wild-type controls (WT), decreased connectivity in the default-mode network is significant for the AD mice relative to WT mice by 6 months of age and is pronounced by 9 months of age. In a second cohort of 20-month-old mice with persistent functional connectivity deficits for AD relative to WT, we assess the impact of two-months of oral treatment with a silent allosteric modulator of mGluR5 (BMS-984923) known to rescue synaptic density. Functional connectivity deficits in the aged AD mice are reversed by the mGluR5-directed treatment. The longitudinal application of fMRI has enabled us to define the preclinical time trajectory of AD-related changes in functional connectivity, and to demonstrate a translatable metric for monitoring disease emergence, progression, and response to synapse-rescuing treatment.

Multimodal identification of the mouse brain using simultaneous Ca2+imaging and fMRI

“…Data were processed using BioImageSuite (BIS) and RABIES (Rodent Automated Bold Improvement of EPI Sequences) 34 software and registered to an in-house template that has been registered to the Allen Institute Common Coordinate Framework Reference Atlas (CCFv3) 35 ( Fig. 2B , Methods ), as we have described previously 30,33,36 .…”

“…Structural and functional MR-images (peach and orange), from each mouse at each acquisition (imaging session), were registered to an in-house reference space ( Methods ). This reference space, created from N = 162 datasets collected on our scanner, see 36 , has been registered to the Allen Institute CCvf3 and Atlas 35 (pink). We use an MRI time-of-flight angiogram (yellow) to capture blood vessels on the cortical surface that also appear in the static WF-Ca 2+ imaging data (green).…”

“…BOLD-fMRI data processing was performed using RABIES (Rodent automated BOLD improvement of EPI sequences 36 ) v0.4.8 (https://rabies.readthedocs.io/en/stable/). All resting-state functional and isotropic MSME structural scans (from all imaging sessions) were input and processed together.…”

“…Nodes belonging to other networks mentioned (e.g. somatosensory) were selected based on the recent comparison across species 36,52,53 .…”

“…Structural images were corrected for inhomogeneities (N3 nonparametric nonuniform intensity normalization). The within-sample anatomical template, created by averaging all structural images following non-linear registration, was registered to our in-house template (using non-linear registration), which has been previously registered to the Allen Atlas reference space CCfv3 33,35,36 .…”