Basic Science and Pathogenesis.

Area of Science:

• Neuroscience
• Genetics
• Toxicology

Background:

• Current mouse models inadequately represent the genetic complexity and clinical variability of late-onset Alzheimer's disease (LOAD).
• The methylenetetrahydrofolate reductase (MTHFR) 677C>T variant and environmental factors like arsenic exposure are implicated in LOAD susceptibility.
• Developing improved models is crucial for advancing preclinical therapeutic development for LOAD.

Purpose of the Study:

• To generate and evaluate novel mouse models that incorporate human LOAD risk alleles and environmental insults.
• To assess the utility of these models in recapitulating key aspects of human LOAD pathology and molecular signatures.
• To identify potential biomarkers and therapeutic targets for LOAD.

Main Methods:

• Generation of LOAD2.Mthfr*677C>T mice homozygous for humanized MTHFR*677C>T, Abeta, APOEe4, and Trem2*R47H alleles.
• Exposure of aged mice to arsenic trioxide in drinking water, followed by longitudinal behavioral, biometric, and endpoint tissue analyses (transcriptomics, proteomics, neuropathology).
• Assessment of arsenic detoxification via urine speciation using LC-ICP-MS.

Main Results:

• MTHFR*677C>T variant led to reduced enzymatic activity and elevated blood homocysteine levels.
• Aged LOAD2.Mthfr*677C>T mice exhibited brain transcriptional and proteomic signatures significantly aligned with human AD.
• Arsenic exposure further enhanced the alignment of transcriptional signatures with human AD, with DMA being the major urinary arsenic species.

Conclusions:

• The Mthfr*677C>T variant and arsenic exposure modify brain molecular profiles, correlating with human LOAD.
• These modified mouse models demonstrate utility in capturing the complexity of human LOAD.
• The study supports the use of these models for discovering LOAD biomarkers and therapeutic targets.