The 677C > T variant in methylenetetrahydrofolate reductase causes morphological and functional cerebrovascular deficits in mice

Vascular contributions to cognitive impairment and dementia (VCID) particularly Alzheimer's disease and related dementias (ADRDs) are increasing; however, mechanisms driving cerebrovascular decline are poorly understood. Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in the folate and methionine cycles. Variants in MTHFR, notably 677 C > T, are associated with dementias, but no mouse model existed to identify mechanisms by which MTHFR677C > T increases risk. Therefore, MODEL-AD created a novel knock-in (KI) strain carrying the Mthfr(677C > T) allele on the C57BL/6J background (Mthfr(677C > T)) to characterize morphology and function perturbed by the variant. Consistent with human clinical data, Mthfr(677C > T) mice have reduced enzyme activity in the liver and elevated plasma homocysteine levels. MTHFR enzyme activity is also reduced in the Mthfr(677C > T) brain. Mice showed reduced tissue perfusion in numerous brain regions by PET/CT as well as significantly reduced vascular density, pericyte number and increased GFAP-expressing astrocytes in frontal cortex. Electron microscopy revealed cerebrovascular damage including endothelial and pericyte apoptosis, reduced luminal size, and increased astrocyte and microglial presence in the microenvironment. Collectively, these data support a mechanism by which variations in MTHFR perturb cerebrovascular health laying the foundation to incorporate our new Mthfr(677C > T) mouse model in studies examining genetic susceptibility for cerebrovascular dysfunction in ADRDs.