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

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Reagan, Alaina M., Christensen, Karen E., Graham, Leah C., Bedwell, Amanda A., Eldridge, Kierra, Speedy, Rachael, Figueiredo, Lucas L., Persohn, Scott C. +5 more·2021·Journal of Cerebral Blood Flow & Metabolism
DOI 10.1101/2021.12.16.472805PMC PMC9670012

Preprint — published as 10.1177/0271678x221122644

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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 677C>T , are associated with dementias, but no mouse model existed to identify mechanisms by which MTHFR 677C>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 as well as critical metabolites in the folate and methionine cycles are 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 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 suggest critical perturbations to cerebrovascular function in Mthfr 677C>T mice supporting its use as a model for preclinical studies of VCID.

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  • B6 mice homozygous or heterozygous for Mthfr677C>T show reduced enzyme activity in both the liver and brain, elevated levels of homocysteine, cerebral blood flow deficits, reduced collagen 4 in the brain, and neurovascular damage by electron microscopy.

    “Supporting a role for MTHFR in the cerebrovascular function, B6 mice homozygous or heterozygous for Mthfr677C > T show reduced enzyme activity in both the liver and brain, elevated levels of homocysteine, cerebral blood flow deficits, reduced collagen 4 in the brain, and neurovascular damage by electron microscopy (Reagan et al., 2021).”

    From Plcg2M28L Interacts With High Fat/High Sugar Diet to Accelerate Alzheimer’s Disease-Relevant Phenotypes in Mice (2022) · cites this paper as Reagan et al., 2021

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Authors
Reagan, A. M., Christensen, K. E., Graham, L. C., Bedwell, A. A., Eldridge, K., Speedy, R., Figueiredo, L. L., Persohn, S. C., Bottiglieri, T., Sasner, M., Territo, P. R., Rozen, R., & Howell, G. R.
Affiliations
  • Jackson Laboratory (US)
  • Research Institute of the McGill University Health Centre (CA)
  • Indiana University Indianapolis (US)
  • Baylor Scott & White Research Institute (US)
  • Tufts University (US)
Corresponding author
Howell, Gareth R.
ORCID
Venue
Journal of Cerebral Blood Flow & Metabolism
Publisher
openRxiv
Published
2021-12-16
Volume
42
Issue
12
Pages
2333-2350
ISSN
0271-678X (ISSN-L)
DOI
10.1101/2021.12.16.472805
PMC
PMC9670012
OpenAlex
W4294176095
Cited by
21
References
0
Citations by year
2026: 6 · 2025: 7 · 2024: 6 · 2023: 1 · 2022: 1
FWCI
2.73
Type
journal article
Language
en
Open access
Locations
  • Journal of Cerebral Blood Flow & Metabolism (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion)
  • The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
Funders
  • BrightFocus Foundation (A2020677F)
  • National Institutes of Health (5u01ag024904-10)
  • Canadian Institutes of Health Research (PJT173521)
  • National Institute on Aging (U01-AG-024904, T32AG062409, U54AG054345)
Topics
  • Health Sciences › Medicine › Rheumatology › Folate and B Vitamins Research
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Keywords
methylenetetrahydrofolate reductase, cerebrovascular dysfunction, vascular cognitive impairment and dementia, Alzheimer's disease and related dementias, knock-in mice, homocysteine, pericytes, astrocytes, microglia, endothelial cell apoptosis, vessel density, cerebral perfusion, folate metabolism, genetic susceptibility
MeSH terms
Positron Emission Tomography Computed Tomography, Animals, Folic Acid, Genotype, Humans, Mice, Inbred C57BL, Genetic Predisposition to Disease, Methylenetetrahydrofolate Reductase (NADPH2), Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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