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

Thathiah, Amantha; Strooper, Bart De

doi:10.1126/scisignal.293re8

Cited by 48 publications

(44 citation statements)

References 101 publications

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“…The Ab42 accumulation associated with the cholinergic dysfunction observed in AD is characterised by diminished acetylcholine release and impaired coupling of the muscarinic acetylcholine receptors with heterotrimeric GTPbinding proteins (G proteins). In an AD transgenic mouse model, it has been shown that abnormal processing of these G proteins alters Tau phosphorylation, leading to neurodegeneration and neuronal loss (Thathiah and De Strooper 2009). Our data seem to suggest that similar interactions, occurring between Ab42 accumulation and Tau phosphorylation, could explain why in the current study SLAI impairment was associated with both Ab42 and p-Tau CSF levels (Haense et al 2010).…”

Section: Discussionsupporting

confidence: 46%

Cerebrospinal fluid levels of Aβ42 relationship with cholinergic cortical activity in Alzheimer’s disease patients

et al. 2012

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The dysfunction of cholinergic neurons is a typical hallmark in Alzheimer's disease (AD). In animal models of AD, fragments of amyloid beta protein (Aβ) and Tau protein are thought to interfere with central cholinergic transmission, specifically with synthesis and release of acetylcholine. Thus, we aimed to investigate whether the cerebrospinal fluid (CSF) levels of Aβ42 and Tau proteins in AD patients could influence physiological central cholinergic activity. In AD patients (n = 19), central cholinergic function was evaluated in vivo by using short afferent latency inhibition (SLAI), and compared to age-matched healthy controls. In the same AD patients, CSF samples were collected through lumbar puncture to obtain individual levels of Aβ42, total Tau (t-Tau) and phosphorylated Tau (p-Tau) (Thr181). SLAI was decreased in AD patients in comparison to age-matched healthy controls. We found that in patients there was a negative correlation between the individual amount of cholinergic activity assessed by SLAI and the CSF levels of Aβ42. On the other hand, there was a positive correlation between the levels of SLAI and CSF p-Tau. No correlation was found when SLAI was analysed together with t-Tau. These results demonstrate that mechanisms of cortical cholinergic activity are altered in patients bearing a pathological CSF hallmark of AD, suggesting that these peptides may have some influence on the cholinergic dysfunction in AD. We suggest that coupling of CSF biomarkers with neurophysiological parameters of central cholinergic function could be important to better detect ongoing mechanisms of neural degeneration in vivo.

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Section: Discussionsupporting

confidence: 46%

Cerebrospinal fluid levels of Aβ42 relationship with cholinergic cortical activity in Alzheimer’s disease patients

et al. 2012

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“…Interactions with the insulin receptor 52 , effects on hypoxia-induced factor HIF-1 (ref. 53), clustering of the G protein-coupled angiotensin type 2 receptor and other mechanisms have also been described 54 . Recently, the cellular prion protein PrP c emerged as a specific receptor for toxic Aβ oligomers 55 , which also has resulted in considerable controversy.…”

Section: An Alternative Interpretation Of Ab Oligomer Toxicitymentioning

confidence: 97%

The toxic Aβ oligomer and Alzheimer's disease: an emperor in need of clothes

2012

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The 'toxic Aβ oligomer' hypothesis has attracted considerable attention among Alzheimer's disease researchers as a way of resolving the lack of correlation between deposited amyloid-β (Aβ) in amyloid plaques-in terms of both amount and location-and cognitive impairment or neurodegeneration. However, the lack of a common, agreed-upon experimental description of the toxic Aβ oligomer makes interpretation and direct comparison of data between different research groups impossible. Here we critically review the evidence supporting toxic Aβ oligomers as drivers of neurodegeneration and make some suggestions that might facilitate progress in this complex field.

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“…these GPCRs. 10 However, the mechanisms by which they activate α-secretases are not always well understood.…”

mentioning

confidence: 99%

5-HT₄ Receptors Constitutively Promote the Non-Amyloidogenic Pathway of APP Cleavage and Interact with ADAM10

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Donneger

Cassier

et al. 2012

ACS Chem. Neurosci.

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In addition to the amyloidogenic pathway, amyloid precursor protein (APP) can be cleaved by α-secretases, producing soluble and neuroprotective APP alpha (sAPPα) (nonamyloidogenic pathway) and thus preventing the generation of pathogenic amyloid-β. However, the mechanisms regulating APP cleavage by α-secretases remain poorly understood. Here, we showed that expression of serotonin type 4 receptors (5-HT 4 Rs) constitutively (without agonist stimulation) induced APP cleavage by the α-secretase ADAM10 and the release of neuroprotective sAPPα in HEK-293 cells and cortical neurons. This effect was independent of cAMP production. Interestingly, we demonstrated that 5-HT 4 receptors physically interacted with the mature form of ADAM10. Stimulation of 5-HT 4 receptors by an agonist further increased sAPPα secretion, and this effect was mediated by cAMP/Epac signaling. These findings describe a new mechanism whereby a GPCR constitutively stimulates the cleavage of APP by α-secretase and promotes the nonamyloidogenic pathway of APP processing. KEYWORDS: Alpha-secretase, Alzheimer's disease, sAPP alpha, serotonin A ccording to the amyloid hypothesis, alteration in synaptic transmission and neuronal loss observed in Alzheimer's disease (AD) mainly result from the formation of toxic amyloid-β (Aβ) oligomers followed by the extracellular accumulation of Aβ aggregates. Aβ is produced by the successive cleavage of a transmembrane amyloid precursor protein (APP) by β-secretase and γ-secretase. 1 In addition to this amyloidogenic pathway, APP can be cleaved by α-secretases, a set of membrane-bound proteases of the ADAM (A disintegrin and metalloprotease) family, generating the soluble APP ectodomain (sAPPα) and a membrane-bound carboxy-terminal fragment (nonamyloidogenic pathway). As α-secretases cleave APP within the Aβ sequence, APP shedding by α-secretases prevents the generation of the pathogenic Aβ peptide. 2,3 Therefore, enhancing α-secretase expression or activity has been considered as a valuable strategy for inhibiting Aβ formation. For instance, it has recently been shown that activation of the transcription of the gene encoding the α-secretase ADAM10, by retinoic acid and sirtuin 1 (SIRT1), reduces Aβ production. 4−6 Previous reports have shown that G protein-coupled receptors (GPCRs) can differentially affect Aβ peptide production by either modulating the cellular trafficking of APP or by influencing the activity and trafficking of α-, β-and γ-secretases. Moreover, both the expression and the stimulation of GPCRs can affect APP metabolism. 7 GPCRs that enhance sAPPα production by stimulating α-secretase activities include the muscarinic M 1 -M 3 receptors, mGlu2 metabotropic glutamate receptor, serotonin 2A (5-HT 2A ) and 5-HT 2C receptors, corticotropin-releasing factor (CRF) receptor 1, purinergic receptor P2X 7 and pituitary adenylate cyclase-activating polypeptide (PACAP) type 1 (PAC 1 ) receptor. 7 These GPCRs are supposed to have a beneficial effect, because sAPPα exerts neuroprotective and neurotro...

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

Cited by 48 publications

References 101 publications

Cerebrospinal fluid levels of Aβ42 relationship with cholinergic cortical activity in Alzheimer’s disease patients

Cerebrospinal fluid levels of Aβ42 relationship with cholinergic cortical activity in Alzheimer’s disease patients

The toxic Aβ oligomer and Alzheimer's disease: an emperor in need of clothes

5-HT₄ Receptors Constitutively Promote the Non-Amyloidogenic Pathway of APP Cleavage and Interact with ADAM10

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

Cited by 48 publications

References 101 publications

Cerebrospinal fluid levels of Aβ42 relationship with cholinergic cortical activity in Alzheimer’s disease patients

Cerebrospinal fluid levels of Aβ42 relationship with cholinergic cortical activity in Alzheimer’s disease patients

The toxic Aβ oligomer and Alzheimer's disease: an emperor in need of clothes

5-HT4 Receptors Constitutively Promote the Non-Amyloidogenic Pathway of APP Cleavage and Interact with ADAM10

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5-HT₄ Receptors Constitutively Promote the Non-Amyloidogenic Pathway of APP Cleavage and Interact with ADAM10