Regional cerebral glucose uptake in the 3xTG model of Alzheimer's disease highlights common regional vulnerability across AD mouse models

Abstract

We have previously used fluorodeoxyglucose (FDG) autoradiography to detect the pattern of metabolic declines in two different transgenic mouse models of fibrillar beta-amyloid pathology in Alzheimer's disease (AD), including the PDAPP mouse, which overexpresses a mutant form of human APP, and the PSAPP mouse, which overexpresses mutant forms of the human APP and PS1 genes. In this study, we used the same approach to study a triple-transgenic (3xTG) model of AD, which overexpresses human APP, PS1 and tau mutations, and progressively develops amyloid plaques, neurofibrillary tangles, and synaptic dysfunction. Densitometric measurements from 55 brain regions were characterized and compared in 2, 12, and 18 month-old 3xTG and wildtype control mice (n = 12/group). By 18 months of age, the 3xTG mice had significant reductions in FDG uptake in every measured brain region, including cortical and subcortical gray matter, cerebellar and brainstem regions. However, regional differences in normalized FDG uptake were apparent in the 2- and 12-month-old 3xTG mice, in a brain network pattern reminiscent of our previous analyses in the other mouse models. This prominently included the posterior cingulate/retrosplenial cortex, as in each previously-analyzed model. Overall, our analyses highlight consistencies in brain glucose uptake abnormalities across multiple mouse models of amyloid-associated pathophysiology. These mouse brain regional changes are homologous to alterations seen in PET scans from human AD patients and could thus be useful biomarkers for early testing of novel interventions.