Hyperhomocysteinemic Alzheimer's mouse model of amyloidosis shows increased brain amyloid β peptide levels

Recent epidemiological and clinical data suggest that elevated serum homocysteine levels may increase the risk of developing Alzheimer's disease (AD), but the underlying mechanisms are unknown. We tested the hypothesis that high serum homocysteine concentration may increase amyloid beta-peptide (A) levels in the brain and could therefore accelerate AD neuropathology. For this purpose, we mated a hyperhomocysteinemic CBStm1Unc mouse carrying a heterozygous dominant mutation in cystathionine-beta-synthase (CBS*) with the APP*/PS1* mouse model of brain amyloidosis. The APP*/PS1*/CBS* mice showed significant elevations of serum homocysteine levels compared to the double transgenic APP*/PS1* model of amyloidosis. Results showed that female (but not male) APP*/PS1*/CBS* mice exhibited significant elevations of A beta 40 and A beta 42 levels in the brain. Correlations between homocysteine levels in serum and brain A beta levels were statistically significant. No increases in beta secretase activity or evidence of neuronal cell loss in the hyperhomocysteinemic mice were found.