Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Sci. Signal., 20 October 2009
Vol. 2, Issue 93, p. re8
[DOI: 10.1126/scisignal.293re8]

REVIEWS

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.

Gloss: 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 G{alpha}q/11 family of G proteins, which facilitate GPCR downstream signaling cascades. Assemblies of the AT2 receptor sequester G{alpha}q/11, preventing it from initiating signaling cascades mediated by other GPCRs. The resulting reduction in G{alpha}q/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 G{alpha}q/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.

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

Citation: A. Thathiah, B. De Strooper, G Protein–Coupled Receptors, Cholinergic Dysfunction, and Aβ Toxicity in Alzheimer’s Disease. Sci. Signal. 2, re8 (2009).

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
GRK5 Deficiency Accelerates {beta}-Amyloid Accumulation in Tg2576 Mice via Impaired Cholinergic Activity.
S. Cheng, L. Li, S. He, J. Liu, Y. Sun, M. He, K. Grasing, R. T. Premont, and W. Z. Suo (2010)
J. Biol. Chem. 285, 41541-41548
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882