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Authors: *H. ZHANG 1 , S. SUN 1 , A. HERREMAN 2 , B. D. STROOPER 2 , I.
BEZPROZVANNY 1 ;
1 UTSouthwestern Med., dallas, TX; 2 K.U.Leuven, LEUVEN, Belgium
Abstract: Alzheimer’s disease (AD) is a progressive and irreversible neurodegenerative
disorder. Mutations in presenilins 1 and 2 (PS1 and PS2) account for 40% of familial AD (FAD)
cases. In the previous studies with mouse embryonic fibroblasts (MEF) cell lines from presenilin
(PS) double-knockout (DKO) mice we demonstrated that presenilins control endoplasmic
reticulum (ER) calcium (Ca 2+ ) levels by acting as passive ER Ca 2+ leak channels and that many
familial Alzheimer's disease (FAD)-linked mutations in presenlins disrupt this function (Tu at al,
2006; Nelson at al, 2007). To determine if presenilins function as ER Ca 2+ leak channels in
neurons, we performed Ca 2+ imaging experiments with hippocampal neuronal cultures from PS
conditional double knockout (cDKO) mice (PS1 floxed/floxed ; PS2 -/-) infected with Cre-encoding
lentiviruses. We observed increased size of ionomycin (IO)-sensitive Ca 2+ pool and increased
caffeine response in PS-null neurons when compared with control cultures. In a series of rescue
experiments we demonstrated that PS1 wild type rescue constructs, but not PS1-FAD reduce the
size of IO-sensitive Ca 2+ pool and caffeine response. We also observed the increased size of
ionomycin (IO)-sensitive Ca 2+ pool and caffeine responses in hippocampal cultures from PS1-
M146V KI mice. These results support the hypothesis that presenilins function as ER Ca 2+ leak
channels in hippocampal neurons. In additional experiments we found that Ryanodine receptors
compensate for loss of ER Ca 2+ leak function of presenilins in hippocampal neurons. Our results
suggest that abnormal ER Ca 2+ homeostasis may play an important role in AD pathogenesis.
Disclosures: H. Zhang, None; S. sun, None; A. Herreman, None; B.D. Strooper, None; I.
bezprozvanny, None.
Poster
527. Beta and Gamma Secretase Function and Metabolism I
Location: South Hall A
Time: Tuesday, October 20, 2009, 8:00 am - 12:00 noon
Program#/Poster#: 527.4/H17
Topic: C.02.d. Beta and gamma secretase, BACE and presenilin
Support: Swiss National Science Foundation (A.I.M. and P.C.F., grant 310000-116652/1)
NCCR “Neural Plasticity and Repair” (P.C.F)
Scholarship Lemanic Neuroscience Program 2007/2008