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

Javier Pacheco-Quinto, Elena B. Rodriguez de Turco, Steven DeRosa, Altovise Howard, Felix Cruz-Sanchez, Kumar Sambamurti, Lorenzo Refolo, Suzana Petanceska, Miguel A. Pappolla

Research output: Contribution to journalArticle

87 Scopus citations

Abstract

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 (Aβ) 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 Aβ40 and Aβ42 levels in the brain. Correlations between homocysteine levels in serum and brain Aβ 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 Aβ seems to be of major importance. By unveiling a link between homocysteine and Aβ levels, these findings advance our understanding on the mechanisms involved in hyperhomocysteinemia as a risk factor for AD.

Original languageEnglish (US)
Pages (from-to)651-656
Number of pages6
JournalNeurobiology of Disease
Volume22
Issue number3
DOIs
StatePublished - Jun 1 2006
Externally publishedYes

    Fingerprint

Keywords

  • Alzheimer's disease
  • Amyloidosis
  • Aβ40
  • Aβ42
  • Brain
  • Hyperhomocysteinemia

ASJC Scopus subject areas

  • Neurology

Cite this

Pacheco-Quinto, J., Rodriguez de Turco, E. B., DeRosa, S., Howard, A., Cruz-Sanchez, F., Sambamurti, K., Refolo, L., Petanceska, S., & Pappolla, M. A. (2006). Hyperhomocysteinemic Alzheimer's mouse model of amyloidosis shows increased brain amyloid β peptide levels. Neurobiology of Disease, 22(3), 651-656. https://doi.org/10.1016/j.nbd.2006.01.005