Cerebral perfusion is elevated in a novel model of aged hAβKI APOE4 mice

Abstract

AbstractBackgroundThe Model Organism Development and Evaluation for Late‐Onset Alzheimer’s Disease (MODEL‐AD) Consortium is developing the next generation of Alzheimer’s disease (AD) models based on human genomic and imaging data. Recently, MODEL‐AD has generated a new human Aβ Knock‐In (hAβKI) mouse carrying the APOE4 allele. APOE4 carriers are at increased risk for AD. Previous studies have demonstrated altered cerebrovascular integrity and function. We examined the cerebrovascular function in the hAβKI APOE4 mice at 18mo of age using perfusion‐weighted magnetic resonance imaging (PWI). We investigated brain‐wide perfusion alterations in conjunction with histopathological vessel painting.MethodsContrast‐enhanced PWI MRI (9.4T) was undertaken from hAβKI APOE4 (n = 6) and WT (n = 5) mice at 18mo of age following tail vein cannulation for Gadolinium infusion. Imaging sequences included: T1‐pre and post‐infusion, PWI (10min) and susceptibility‐weighted imaging (SWI) for blood extravasation and iron content. All data were processed using JIM v9 software for maps of cerebral blood flow (CBF), volumes (CBV), time to peak, mean transit time and dynamic susceptibility measures for blood‐brain barrier dysfunction. Manual regions of interest (ROI) were performed for cortex, temporal lobe cortex, dorsal hippocampus and thalamus, and semi‐automatic 30+ regions based on the Allen mouse brain atlas. At the end of the in vivo experiments all mice underwent vessel painting followed by microscopic analyses.ResultsCompared to WT mice at 18mo of age, hAβKI APOE4 mice exhibited elevated CBF in virtually all regions examined. CBF was elevated approx. 16%, 11%, 4% and 23% in the cortex, hippocampus, thalamus and temporal lobe cortex, respectively. CBF was significantly elevated in the retrosplenial and temporal lobe cortices (p<0.05). CBV was also significantly increased in temporal lobe. Ongoing analyses will correlate vascular network measures (density, junctions, length) to PWI metrics as well as to hAβKI only mice.ConclusionsThe 18mo hAβKI APOE4 mouse compared to WT exhibited consistent brain‐wide elevations in cerebrovascular measures. This increase may represent a compensatory mechanism to maintain decreased metabolism that occurs with aging. The MODEL‐AD consortium (UCI/IUSM/JAX) continues to develop new and novel AD mouse models. All data will be made available to AD researchers via the Sage Knowledge Network (https://adknowledgeportal.synapse.org/).