G-protein α-subunit levels in hippocampus and entorhinal cortex of brains staged for Alzheimer’s disease neurofibrillary and amyloid pathologies

García-Jiménez, Angela; Fastbom, Johan; Ohm, Thomas G.; Cowburn, Richard F.

doi:10.1097/00001756-200308060-00025

Cited by 6 publications

(3 citation statements)

References 24 publications

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“…Gα q/11 abundance appears to remain unaltered in the AD brain (55)(56)(57). Moreover, Gα q/11stimulated signaling cascades are critical in neuronal communication, synaptic plasticity, and neuronal survival (58,59).…”

Section: Muscarinic Receptor Signaling In Alzheimer's Diseasementioning

confidence: 99%

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

Thathiah

Strooper

2009

Sci. Signal.

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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.

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Section: Muscarinic Receptor Signaling In Alzheimer's Diseasementioning

confidence: 99%

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

Thathiah

Strooper

2009

Sci. Signal.

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“…1994; Li et al . 1996; Garcia‐Jimenez et al . 2003) and regional‐specific changes may occur (O'Neill 1994; Kolasa et al .…”

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confidence: 99%

“…It has been suggested that the Ab-induced G protein activation may be an early step in the mechanism of Ab action . Several studies indicated that the overall levels of G-proteins are largely preserved in AD (Ross et al 1993;Li et al 1996;Garcia-Jimenez et al 2002), although subunit (O'Neill et al 1994;Li et al 1996;Garcia-Jimenez et al 2003) and regional-specific changes may occur (O'Neill 1994;Kolasa et al 2000), but the function of G-proteins seemed to be impaired with the progression of AD (O'Neill 1994;Wang and Friedman 1994;Garcia-Jimenez 2002). In this study we determined the effects of Ab(1-42), Ab(1-40), Ab(25-35), their mixtures and their complexes with zinc on [ 35 S]GTP binding in rat brain cortical membranes and correlated the biological activity changes with structural alterations.…”

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confidence: 99%

Enhanced G‐protein activation by a mixture of Aβ(25–35), Aβ(1–40/42) and zinc

Molnár

Kovacs

Laczkó

et al. 2004

Journal of Neurochemistry

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b-Amyloid peptides (Abs) bind to several G-protein coupled receptor proteins and stimulate GTPase activity in neurons. In this study we determined the effects of Ab(1-42), Ab(1-40), and their mixtures on [ 35 S]GTP binding in rat brain cortical membranes in the absence and presence of zinc. We found that the Abs alone induced a concentration-dependent activation of G-proteins (IC 50 10 )6 M), while aggregated Ab fibrils only affected GTP binding at concentrations above 10 )5 M. Mixing Ab(25-35) with Ab(1-42) or Ab(1-40) induced a several-fold increase in GTP-binding. This potentiation followed a bell shaped curve with a maximum at 50 : 50 ratios. No potentiating effect could be seen by mixing Ab(1-40) and Ab(1-42) or highly aggregated Abs. Zinc had no effect on Ab(1-40/42) but strongly potentiated the Ab(25-35) or the mixed peptides-induced GTP-binding. Changes in secondary structure accompanied the mixed peptides or the peptide/zinc complexes induced potentiation, revealing that structural alterations are behind the increased biological action. These concentration dependent potentiating effects of zinc and the peptide mixtures could be physiologically important at brain regions where peptide fragments and/or zinc are present at elevated concentrations.

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