Reduction of Aβ accumulation in the Tg2576 animal model of Alzheimer’s disease after oral administration of the phosphatidyl-inositol kinase inhibitor wortmannin 1
- S. J. HAUGABOOK,
- T. LE,
- D. YAGER,
- B. ZENK,
- B. M. HEALY,
- E. A. ECKMAN,
- C. PRADA,
- L. YOUNKIN,
- P. MURPHY,
- I. PINNIX,
- L. ONSTEAD,
- K. SAMBAMURTI,
- T. E. GOLDE,
- D. DICKSON,
- S. G. YOUNKIN and
- C. B. ECKMAN2
- Mayo Clinic Jacksonville, Jacksonville, Florida 32224, USA
- ↵Correspondence: 2Correspondence: Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. E-mail: Eckman{at}mayo.edu
SPECIFIC AIMS
Thedeposition of Aβ in the form of senile plaques in sufficient quantity is a pathological hallmark of Alzheimer’s disease. In this study we examine whether the phosphatidyl-inositol kinase inhibitor wortmannin can reduce Aβ accumulation both in vitro and in vivo.
PRINCIPAL FINDINGS
1. Wortmannin reduces extracellular Aβ accumulation in cell culture
In cell-based screens, we identified wortmannin, a specific inhibitor of phosphatidyl-inositol kinases, as an Aβ-lowering agent. Wortmannin treatment of CHO 2B7 cells results in a dose-dependent reduction in Aβ40 and Aβ42. Both cell viability assays and washout experiments indicate that this reduction in Aβ accumulation is not simply due to a toxic effect of the drug.
2. Wortmannin treatment reduces sAPPα and increases carboxyl-terminal fragments of βAPP
Aβ is formed by the proteolytic cleavage of a larger precursor molecule, referred to as βAPP. Large secreted derivatives (sAPP) are normally produced and secreted into the conditioned medium, whereas carboxyl-terminal fragments of βAPP (CTFs), some of which contain the entire Aβ sequence, are found within the cell. Consistent with a previous report by Petanseska and Gandy, who used a different cell line, we observed a reduction in the amount of sAPPα in the medium and an increase in the levels of CTFs in the cell after wortmannin treatment. We interpret these data to suggest that wortmannin may be influencing Aβ accumulation in the extracellular milieu by altering trafficking of the βAPP. For example, …
