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Efficient Purification and LC-MS/MS-based Assay Development for Ten-Eleven Translocation-2 5-Methylcytosine Dioxygenase
Published on: October 15, 2018
The 677C > T variant in methylenetetrahydrofolate reductase causes morphological and functional cerebrovascular
Alaina M Reagan1, Karen E Christensen2, Leah C Graham1
1The Jackson Laboratory, Bar Harbor, ME, USA.
Abstract:
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 MTHFR increases risk. Therefore, MODEL-AD created a novel knock-in (KI) strain carrying the Mthfr allele on the C57BL/6J background (Mthfr) to characterize morphology and function perturbed by the variant. Consistent with human clinical data, Mthfr mice have reduced enzyme activity in the liver and elevated plasma homocysteine levels. MTHFR enzyme activity is also reduced in the Mthfr 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 mouse model in studies examining genetic susceptibility for cerebrovascular dysfunction in ADRDs.
Insights
New mouse models reveal how MTHFR gene variants impair brain blood vessels, increasing risk for cognitive decline and dementia. This research helps understand cerebrovascular dysfunction in Alzheimer's disease and related dementias.
Area of Science:
- Neuroscience
- Genetics
- Cardiovascular Science
Background:
- Vascular contributions to cognitive impairment and dementia (VCID) are a growing concern, yet the underlying mechanisms of cerebrovascular decline remain unclear.
- Genetic variants in methylenetetrahydrofolate reductase (MTHFR), particularly the 677C>T variant, are linked to dementia, but a suitable animal model was lacking to study these effects.
Purpose of the Study:
- To create and characterize a novel knock-in mouse model (Mthfr KI) that mimics human MTHFR variants.
- To investigate the impact of MTHFR variants on cerebrovascular morphology, function, and cellular changes in the brain.
Main Methods:
- Generated a C57BL/6J knock-in mouse strain carrying the Mthfr variant.
- Assessed MTHFR enzyme activity, plasma homocysteine levels, and tissue perfusion using PET/CT.
- Quantified vascular density, pericyte number, and astrocyte activation (GFAP) in the frontal cortex.
- Utilized electron microscopy to examine cerebrovascular ultrastructure.
Main Results:
- Mthfr KI mice exhibited reduced MTHFR enzyme activity in the liver and brain, with elevated plasma homocysteine.
- PET/CT revealed reduced perfusion in multiple brain regions.
- Significant decreases in vascular density and pericyte numbers were observed, alongside increased GFAP-expressing astrocytes.
- Electron microscopy showed endothelial and pericyte apoptosis, reduced vessel lumen size, and altered microglial and astrocyte presence.
Conclusions:
- MTHFR gene variants perturb cerebrovascular health, leading to reduced perfusion and structural damage.
- This Mthfr mouse model provides a valuable tool for studying the genetic susceptibility to cerebrovascular dysfunction in Alzheimer's disease and related dementias (ADRDs).
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