Hyperhomocysteinemic Alzheimer's mouse model of amyloidosis shows increased brain amyloid beta 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 (Abeta) levels in the brain and could therefore accelerate AD neuropathology. For this purpose, we mated a hyperhomocysteinemic CBS(tm1Unc) 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 Abeta40 and Abeta42 levels in the brain. Correlations between homocysteine levels in serum and brain Abeta levels were statistically significant. No increases in beta secretase activity or evidence of neuronal cell loss in the hyperhomocysteinemic mice were found. The causes of neuronal dysfunction and degeneration in AD are not fully understood, but increased production of Abeta seems to be of major importance. By unveiling a link between homocysteine and Abeta levels, these findings advance our understanding on the mechanisms involved in hyperhomocysteinemia as a risk factor for AD.
Pacheco-Quinto
Javier
J
Neuroscience Center of Excellence, LSU Health Science Center, 2020 Gravier Street, Suite D, New Orleans, LA 70112, USA.
Rodriguez de Turco
Elena B
EB
DeRosa
Steven
S
Howard
Altovise
A
Cruz-Sanchez
Felix
F
Sambamurti
Kumar
K
Refolo
Lorenzo
L
Petanceska
Suzana
S
Pappolla
Miguel A
MA
D000544:Alzheimer Disease / Q000097:blood* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000686:Amyloidosis / Q000097:blood* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001923:Brain Chemistry / Q000502:physiology*; D002452:Cell Count; D003541:Cystathionine beta-Synthase / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006710:Homocysteine / Q000097:blood*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009474:Neurons / Q000473:pathology; D016133:Polymerase Chain Reaction; D012737:Sex Factors
D016229:Amyloid beta-Peptides; D006710:Homocysteine; D003541:Cystathionine beta-Synthase