Lectures
April 3th Seminar-Jie Shen
Time：2015-03-12KeyWord：
Presenilin and Alzheimer’s Disease
Speaker: Jie Shen, Ph.D., Professor
Center for Neurologic Diseases, Brigham and Women's Hospital
Program in Neuroscience, Harvard Medical School
Abstract:
Mutations in presenilin-1 (PSEN1) are the major cause of familial Alzheimer’s disease (FAD). How PSEN1 mutations perturb Presenilin-1 (PS1) function in the brain to produce FAD is unresolved. To determine the impact of pathogenic mutations on PS1 function in vivo, we generated two independent Psen1 knock-in (KI) mice in which the FAD mutation L435F or C410Y was introduced into the genomic Psen1 locus. Surprisingly, homozygous KI/KI mice display perinatal lethality and developmental defects indistinguishable from those of Psen1-null mice. Psen1 mRNA levels are unchanged in KI/KI mice, but PS1 endoproteolysis is impaired. In vitro γ-secretase assay revealed that γ-secretase-mediated cleavage of APP, Notch and N-Cadherin is abolished in KI/KI embryonic brains and reduced (~50%) in KI/+ brains. Levels of mouse endogenous Aβ40 and Aβ42 are reduced in the adult cerebral cortex of KI/+ mice, and the Aβ42/40 ratio is increased at ~15% due to the greater reduction of Aβ40. Similarly, levels of human Aβ derived from transgenic mice are also reduced in the cerebral cortex of KI/+ mice, and the Aβ42/40 ratio is increased, leading to accelerated amyloid deposition. Using three behavioral paradigms assessing hippocampal memory, we found that spatial memory and pattern completion are impaired. Electrophysiological analysis of the hippocampal Schaeffer collateral and commissural/associational synapses showed reduced short-term and long-term synaptic plasticity. Stereological analysis revealed that the PSEN1 mutation causes age-dependent neurodegeneration, increased apoptosis and gliosis. Collectively, our results demonstrate that pathogenic PSEN1 mutations produce a full spectrum of AD related phenotypes through a loss of Presenilin function mechanism.
Host: Prof. Yigong Shi
Date: 10:30AM-11:30AM, April 3rd (Friday)
Venue: Room143, New Biology Building
