G protein-coupled receptors, cholinergic dysfunction, and Abeta toxicity in Alzheimer's disease.
The beta-amyloid (Abeta) peptide is associated with the pathogenesis of Alzheimer's disease (AD). Evidence gathered over the last two decades suggests that the gradual accumulation of soluble and insoluble Abeta peptide species triggers a cascade of events that leads to the clinical manifestation of AD. Abeta accumulation has also been associated with the cholinergic dysfunction observed in AD, which is characterized by diminished acetylcholine release and impaired coupling of the muscarinic acetylcholine receptors (mAChRs) to heterotrimeric GTP-binding proteins (G proteins). Although the mechanism of Abeta-mediated toxicity is not clearly understood, evidence shows that Abeta accumulation has an effect on the oligomerization of the angiotensin II (AngII) AT(2) (angiotensin type 2) receptor and sequestration of the Galpha(q/11) family of G proteins. Sequestration of Galpha(q/11) results in dysfunctional coupling and signaling between M(1) mAChR and Galpha(q/11) and accompanies neurodegeneration, tau phosphorylation, and neuronal loss in an AD transgenic mouse model. Collectively, these results provide a putative link among Abeta toxicity, AT(2) receptor oligomerization, and disruption of the signaling pathway through M(1) mAChR and Galpha(q/11) and potentially contribute to our understanding of the cholinergic deficit observed in AD.
Thathiah
Amantha
A
Molecular and Developmental Genetics, VIB, Leuven, Belgium. amantha.thathiah@med.kuleuven.be
De Strooper
Bart
B
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D006801:Humans; D018384:Oxidative Stress; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D011976:Receptors, Muscarinic / Q000378:metabolism*; D015398:Signal Transduction
D016229:Amyloid beta-Peptides; D043562:Receptors, G-Protein-Coupled; D011976:Receptors, Muscarinic