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

Sci. Signal.  20 Oct 2009:
Vol. 2, Issue 93, pp. re8
DOI: 10.1126/scisignal.293re8

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Alzheimer’s disease (AD) is the most common neurodegenerative disorder afflicting the elderly. Neuropathologically, the AD brain is characterized by amyloid plaques, which are mainly composed of the β-amyloid protein (Aβ) and neurofibrillary tangles (NFTs), which are comprised of hyperphosphorylated aggregates of the tau protein. Few treatments are available, but acetylcholinesterase inhibitors, which increase acetylcholine concentrations in the brain, provide some beneficial effects. Abnormal accumulation of Aβ in the brain is believed to drive disease progression. Although the mechanism of Aβ-mediated toxicity is not clearly understood, new studies provide insight into the effect that Aβ accumulation has on the clustering of a heterotrimeric GTP-binding protein (G protein)–coupled receptor (GPCR), the angiotensin type 2 (AT2) receptor, and the resulting effect on the Gαq/11 family of G proteins, which facilitate GPCR downstream signaling cascades. Assemblies of the AT2 receptor sequester Gαq/11, preventing it from initiating signaling cascades mediated by other GPCRs. The resulting reduction in Gαq/11 binding and signaling by the M1 muscarinic acetylcholine receptor (mAChR) has now been shown to accompany neurodegeneration in an AD mouse model. Thus, these studies provide a potential link between Aβ toxicity, AT2 receptor clustering, and disruption of the M1 mAChR and Gαq/11 signaling pathways, and they contribute to our understanding of the pathogenesis of AD. This Review with 1 figure and 100 citations highlights GPCR-mediated mechanisms of Aβ-induced toxicity in AD.