Premium
O1‐05‐05: GPR3 modulation of the Gamma‐secretase complex and Abeta generation in Alzheimer's disease
Author(s) -
Thathiah Amantha,
De Strooper Bart,
Horre Katrien
Publication year - 2011
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2011.05.260
Subject(s) - genetically modified mouse , amyloid precursor protein , transgene , microbiology and biotechnology , chemistry , amyloid (mycology) , g protein coupled receptor , signal transduction , neuroscience , alzheimer's disease , biology , biochemistry , medicine , disease , inorganic chemistry , gene
Background:G-protein-coupled receptors (GPCRs) are involved in numerous key neurotransmitter systems that are disrupted in the brains of Alzheimer’s disease (AD) patients. GPCRs also influence the amyloid cascade at multiple stages of proteolysis of the amyloid precursor protein (APP) and subsequent degradation of the amyloid-beta (Aß) peptide. Methods: We crossed an AD transgenic mouse model with Gpr3 mice and assessed Abeta peptide generation by ELISA, amyloid plaque burden by immuno-histochemical analysis and performed behavioral studies to assess the cognitive deficits in an AD transgenic model in the absence of GPR3. Results: Utilizing the APP/PS1 transgenic mouse, we determined that genetic ablation of GPR3 leads to a dramatic decrease in Abeta peptide generation whereas overexpression of GPR3 leads to an accumulation of Abeta. Further immuno-histochemical analysis of APP/PS1/Gpr3 mouse brains indicates that the absence of GPR3 leads to a decrease in the amyloid plaque burden. Behavioural studies also suggest alleviation of the cognitive deficits in this AD mouse model. Conclusions: Although classic G proteinsignaling does not appear to be involved in the GPR3-mediated increase in Abeta generation, preliminary studies suggest that alternate mechanisms coordinated through the recruitment of scaffolding and signaling intermediates to GPR3 play an important role in the stimulation of Abeta release. These studies provide crucial mechanistic insight into regulation of the gammasecretase-mediated cleavage of the APP by GPR3 and thereby provide a potential therapeutic approach to modulate the gamma-secretase complex during AD progression.