Presenilin 2 familial Alzheimer's disease mutations result in partial loss of function and dramatic changes in Aβ 42/40 ratios
Version of Record online: 9 DEC 2004
Journal of Neurochemistry
Volume 92, Issue 2, pages 294–301, January 2005
How to Cite
Walker, E. S., Martinez, M., Brunkan, A. L. and Goate, A. (2005), Presenilin 2 familial Alzheimer's disease mutations result in partial loss of function and dramatic changes in Aβ 42/40 ratios. Journal of Neurochemistry, 92: 294–301. doi: 10.1111/j.1471-4159.2004.02858.x
- Issue online: 9 DEC 2004
- Version of Record online: 9 DEC 2004
- Received July 13, 2004; revised manuscript received September 2, 2004; accepted September 3, 2004.
- familial Alzheimer's disease;
- presenilin 2;
Gene knockout studies in mice suggest that presenilin 1 (PS1) is the major γ-secretase and that it contributes disproportionately to amyloid β (Aβ) peptide generation from β-amyloid precursor protein (APP), whereas PS2 plays a more minor role. Based on this and other observations we hypothesized that familial Alzheimer's disease (FAD) mutations in PS2 would have a dramatic effect on function in order to have an observable effect on Aβ levels in the presence of normal PS1 alleles. Only four of the eight reported FAD mutations in PS2 have altered function in vitro suggesting that the other variants represent rare polymorphisms rather than disease-causing mutations. In support of our hypothesis, the four verified PS2 FAD mutations cause substantial changes in the Aβ 42/40 ratio, comparable with PS1 mutations that cause very-early-onset FAD. Most of the PS2 mutations also cause a significant decrease in Aβ 40, APP C-terminal fragment (CTF)γ and Notch intracellular domain (NICD) production suggesting that they are partial loss of function mutations. PS2 M239V, its PS1 homolog M233V, and other FAD mutations within transmembrane (TM) 5 of PS1 differentially affect CTFγ and NICD production suggesting that TM5 of PS are important for γ-secretase cleavage of APP but not Notch.