| First Author | Guo Q | Year | 2013 |
| Journal | PLoS One | Volume | 8 |
| Issue | 11 | Pages | e80706 |
| PubMed ID | 24278307 | Mgi Jnum | J:209782 |
| Mgi Id | MGI:5568687 | Doi | 10.1371/journal.pone.0080706 |
| Citation | Guo Q, et al. (2013) Modeling Alzheimer's Disease in mouse without mutant protein overexpression: cooperative and independent effects of Abeta and tau. PLoS One 8(11):e80706 |
| abstractText | BACKGROUND: Alzheimer's disease (AD), the most common cause of dementia in the elderly, has two pathological hallmarks: Abeta plaques and aggregation of hyperphosphorylated tau (p-tau). Abeta is a cleavage product of Amyloid Precursor Protein (APP). Presenilin 1 (PS1) and presenilin 2 (PS2) are the catalytic subunit of gamma-secretase, which cleaves APP and mediates Abeta production. Genetic mutations in APP, PSEN1 or PSEN2 can lead to early onset of familial AD (FAD). Although mutations in the tau encoding gene MAPT leads to a subtype of frontotemporal dementia and these mutations have been used to model AD tauopathy, no MAPT mutations have been found to be associated with AD. RESULTS: To model AD pathophysiology in mice without the gross overexpression of mutant transgenes, we created a humanized AD mouse model by crossing the APP and PSEN1 FAD knock-in mice with the htau mice which express wildtype human MAPT genomic DNA on mouse MAPT null background (APP/PS1/htau). The APP/PS1/htau mice displayed mild, age-dependent, Abeta plaques and tau hyperphosphorylation, thus successfully recapitulating the late-onset AD pathological hallmarks. Selected biochemical analyses, including p-tau western blot, gamma-secretase activity assay, and Abeta ELISA, were performed to study the interaction between Abeta and p-tau. Subsequent behavioral studies revealed that the APP/PS1/htau mice showed reduced mobility in old ages and exaggerated fear response. Genetic analysis suggested that the fear phenotype is due to a synergic interaction between Abeta and p-tau, and it can be completely abolished by tau deletion. CONCLUSION: The APP/PS1/htau model represents a valuable and disease-relevant late-onset pre-clinical AD animal model because it incorporates human AD genetics without mutant protein overexpression. Analysis of the mice revealed both cooperative and independent effects of Abeta and p-tau. |
