Hyperhomocysteinemic Mice Show Cognitive Impairment Without Features of Alzheimer's Disease Phenotype

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.

Ameliorative Effect of a Selective Endothelin ETAReceptor Antagonist in Rat Model of L-Methionine-induced Vascular Dementia

“…Recent studies have indicated that experimental hyperhomocysteinemia resulting from chronic administration of L-methionine produces cognitive impairment [41,42]. This is further supported by earlier findings [12] and results of the present investigation whereby L-methionine treated rats have shown a significant decrease in MWM performance.…”

Heart failure and cognitive dysfunction

“…Mice with hyperhomocysteinemia have cognitive impairment [118,119]. In cultured astrocytes, homocysteine resulted in induction of reactive oxygen species, which led to alteration in the actin cytoskeleton of astrocytes but not co-cultured neurons [120].…”

Hyperhomocysteinemia: Impact on Neurodegenerative Diseases

“…They also found an increased activity of metalloproteinase 2 (MMP2) and MMP9 systems that showed pathogenesis of cerebral haemorrhage. In one of the studies by Rhodehouse et al [43] in 2013, a Hhcy mice model showed cognitive impairment without features of AD phenotype.…”