G Protein–Coupled Receptors, Cholinergic Dysfunction, and Aβ Toxicity in Alzheimer’s Disease

Amantha Thathiah^* and Bart De Strooper^*

Molecular and Developmental Genetics, VIB, Leuven, Belgium, and the Center for Human Genetics, K.U. Leuven, Leuven, Belgium.

Abstract: The β-amyloid (Aβ) 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 Aβ peptide species triggers a cascade of events that leads to the clinical manifestation of AD. Aβ 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 Aβ-mediated toxicity is not clearly understood, evidence shows that Aβ accumulation has an effect on the oligomerization of the angiotensin II (AngII) AT₂ (angiotensin type 2) receptor and sequestration of the G_q/11 family of G proteins. Sequestration of G_q/11 results in dysfunctional coupling and signaling between M₁ mAChR and G_q/11 and accompanies neurodegeneration, tau phosphorylation, and neuronal loss in an AD transgenic mouse model. Collectively, these results provide a putative link among Aβ toxicity, AT₂ receptor oligomerization, and disruption of the signaling pathway through M₁ mAChR and G_q/11 and potentially contribute to our understanding of the cholinergic deficit observed in AD.

* Corresponding authors. E-mail, bart.destrooper{at}med.kuleuven.be or amantha.thathiah{at}med.kuleuven.be.

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