Affiliations: [a] Department of Biological Sciences, Idaho State University, Pocatello, ID, USA | [b] Geriatric Research Educational and Clinical Center (GRECC), Veterans Administration Puget Sound Health Care System, Seattle, WA, USA | [c] Division of Gerontology and Geriatric Medicine, Department of Internal Medicine, University of Washington School of Medicine, Seattle, WA, USA | [d] ISU Biomedical Research Institute, Idaho State University, Pocatello, ID, USA
Correspondence:
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Correspondence to: Shawn E. Bearden, Ph.D, Idaho State University, Biological Sciences, 921 S. 8th Ave stop 8007, Pocatello, ID, 83209-8007, USA. Tel.: +1 208 282 6269; Fax: +1 208 282 4570; E-mail: bearshaw@isu.edu.
Abstract: Hyperhomocysteinemia (HHcy) is associated with cognitive impairment and Alzheimer's disease. Whether this association is mechanistic remains unclear. Here, we used a mouse model to test the hypothesis that HHcy increases levels of amyloid-β (Aβ) transporters in microvessels that form the blood-brain barrier, elevates Aβ content (Aβ40 and Aβ42) in the brain, and impairs cognitive performance. Mice with HHcy and age-matched, non-HHcy controls (Ctrl) were studied in two age groups: adult (6.2 ± 0.4 months of age) and old (19 ± 2.0 months of age). Levels of Aβ transporters, RAGE, LRP1, and Pgp, were not different between HHcy and Ctrl mice. Though there was an increase in overall brain Aβ levels with age, there were no differences between HHcy and Ctrl groups in cortex, hippocampus, or midbrain/diencephalon. Despite the lack of difference in Aβ, old mice with HHcy showed significant cognitive impairment on Morris water maze tests compared with Ctrl mice. We conclude that HHcy leads to cognitive impairment without many of the changes currently thought to be relevant to promoting the AD phenotype.
