Amyloid β synaptotoxicity is Wnt‐PCP dependent and blocked by fasudil

Sellers, Katherine J.; Elliott, Carl; Jackson, Joshua D.; Ghosh, Anshua; Ribé, Elena M.; Rojo, Ana I.; Jarosz-Griffiths, Heledd; Watson, Iain A.; Xia, Weiming; Semënov, Mikhail; Morin, Peter J.; Hooper, Nigel M.; Porter, Rod A.; Preston, Jane E.; Al‐Shawi, Raya; Baillie, George S.; Lovestone, Simon; Cuadrado, Antonio; Harte, Michael K.; Simons, Paul; Srivastava, Deepak P.; Killick, Richard

doi:10.1016/j.jalz.2017.09.008

Cited by 87 publications

(112 citation statements)

References 49 publications

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“…Aβ synaptoxicity is Dkk1-dependent 12 , 24 and also appears to be APP-dependent 25 . The results described above show that APP enhances the effects of Dkk1, changing the balance of Wnt signalling away from the Wnt-β-catenin pathway and towards Wnt-PCP signalling.…”

Section: Resultsmentioning

confidence: 98%

“…Increased expression of Dkk1 has been shown in post-mortem AD brain and in animal models of Aβ pathology 11 , and its expression is induced in neuronally enriched cultures as an early response to Aβ 10 . Dkk1 drives multiple aspects of Aβ-mediated neurotoxicity, including synapse loss through effects on Wnt signalling 12 – 14 . Dkk1 is known principally as an inhibitor of the Wnt-β-catenin, or canonical Wnt, pathway.…”

Section: Introductionmentioning

confidence: 99%

“…Dkk1 is known principally as an inhibitor of the Wnt-β-catenin, or canonical Wnt, pathway. However, we have demonstrated that concomitant with this antagonism Dkk1-induced activation of the non-canonical Wnt-planar cell polarity (Wnt-PCP) pathway is also required for Aβ-driven synapse disassembly to occur 14 . At synapses, the Wnt-β-catenin and Wnt-PCP Wnt pathways have opposing actions which, under normal physiological conditions, work in concert to maintain synaptic homeostasis 15 – 19 .…”

Section: Introductionmentioning

confidence: 99%

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A role for APP in Wnt signalling links synapse loss with β-amyloid production

et al. 2018

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In Alzheimer’s disease (AD), the canonical Wnt inhibitor Dickkopf-1 (Dkk1) is induced by β-amyloid (Aβ) and shifts the balance from canonical towards non-canonical Wnt signalling. Canonical (Wnt-β-catenin) signalling promotes synapse stability, while non-canonical (Wnt-PCP) signalling favours synapse retraction; thus Aβ-driven synapse loss is mediated by Dkk1. Here we show that the Amyloid Precursor Protein (APP) co-activates both arms of Wnt signalling through physical interactions with Wnt co-receptors LRP6 and Vangl2, to bi-directionally modulate synapse stability. Furthermore, activation of non-canonical Wnt signalling enhances Aβ production, while activation of canonical signalling suppresses Aβ production. Together, these findings identify a pathogenic-positive feedback loop in which Aβ induces Dkk1 expression, thereby activating non-canonical Wnt signalling to promote synapse loss and drive further Aβ production. The Swedish familial AD variant of APP (APPSwe) more readily co-activates non-canonical, at the expense of canonical Wnt activity, indicating that its pathogenicity likely involves direct effects on synapses, in addition to increased Aβ production. Finally, we report that pharmacological inhibition of the Aβ-Dkk1-Aβ positive feedback loop with the drug fasudil can restore the balance between Wnt pathways, prevent dendritic spine withdrawal in vitro, and reduce Aβ load in vivo in mice with advanced amyloid pathology. These results clarify a relationship between Aβ accumulation and synapse loss and provide direction for the development of potential disease-modifying treatments.

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Section: Resultsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A role for APP in Wnt signalling links synapse loss with β-amyloid production

et al. 2018

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“…Potential molecular mechanisms linking Aß and tau to synapse and circuit dysfunction include calcium dysregulation and calcineurin activation, which are known to contribute to Aß toxicity and spine collapse in vitro and in vivo and have recently been linked to tau mediated synapse impairment (Hudry et al, 2012;Kuchibhotla et al, 2008;Mattson et al, 1992;Wu et al, 2010;Yin et al, 2016;Zempel et al, 2010). Abnormal activation of synaptic receptors by Aß has also been shown to induce activation of kinases including Fyn and GSK3-ß which affect tau phosphorylation and synapse collapse (Ittner et al, 2010;Lovestone et al, 2014;Marzo et al, 2016;Purro et al, 2012;Roberson et al, 2011;Sellers et al, 2018;Small and Duff, 2008). Our RNAseq results add to the literature implicating cellular prion protein at the interface between Aß and tau as increases in PrPc mRNA in MAPT-AD mice was the largest change observed with RNAseq and these levels recover with tau suppression.…”

Section: Discussionmentioning

confidence: 99%

Reducing tau ameliorates behavioural and transcriptional deficits in a novel model of Alzheimer’s disease

McQueen

et al. 2018

Preprint

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SummaryOne of the key knowledge gaps blocking development of effective therapeutics for Alzheimer's disease (AD) is the lack of understanding of how amyloid beta (Aß) and tau cooperate in causing disease phenotypes. Within a mouse tau deficient background, we probed the molecular, cellular and behavioural disruption triggered by wild-type human tau's influence on human Aß-induced pathology.We find that Aß and tau work cooperatively to cause a hyperactivity phenotype and to cause downregulation of gene transcription including many involved in synaptic function. In both our mouse model and in human post-mortem tissue, we observe accumulation of pathological tau in synapses, supporting the potential importance of synaptic tau. Importantly, tau depletion in the mice, initiated after behavioural deficits emerge, was found to correct behavioural deficits, reduce synaptic tau levels, and substantially reverse transcriptional perturbations, suggesting that lowering tau levels, particularly at the synapse, may be beneficial in AD.. CC-BY 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/393405 doi: bioRxiv preprint first posted online Aug. 16, 2018; 2 Highlights -Expression of human familial Alzheimer's associated mutant amyloid precursor protein and presenillin 1 with wild-type human tau in the absence of endogenous tau in a novel MAPT-AD mouse model results in behavioural deficits and downregulation of genes involved in synaptic function -Tau is present in pre and postsynaptic terminals in MAPT-AD mice and human AD brain. In mice, lowering synaptic tau levels was associated with improved cognition and recovered gene expression.-These data suggest that Aß and tau act cooperatively in impairing synaptic function and that lowering tau at synapses could be a beneficial therapeutic approach in AD.

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“…Our data, however, suggested that Rhoc did not play a significant role in microglia proinflammatory activation and microglia-induced neurotoxicity. In this context, ROCK inhibition by Y27632 or fasudil attenuates microglia activation, promoting some functional recovery in animal models for different neurological conditions (Mueller et al, 2005, Chen et al, 2013, Chong et al, 2017, Sellers et al, 2018. Because Rhoa is likely to exert its control over microglia immune activity through several other downstream effectors besides ROCK, which activation can also be regulated independently of Rhoa (Julian and Olson, 2014), these studies are not very informative concerning Rhoa regulation of microglial function.…”

Section: Discussionmentioning

confidence: 99%

Microglia dysfunction caused by the loss of Rhoa disrupts neuronal physiology and leads to neurodegeneration

Socodato¹,

Portugal²,

Canedo³

et al. 2017

Preprint

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Nervous tissue homeostasis requires regulation of microglia activity. Using conditional gene targeting in mice, we demonstrate that genetic ablation of the small GTPase Rhoa in adult microglia is sufficient to trigger spontaneous microglia activation producing a neurological phenotype (including synapse and neuron loss, impairment of LTP, formation of ß-amyloid plaques and memory deficits). Mechanistically, loss of Rhoa in microglia triggers Src activation and Src-mediated Tnf production, leading to excitotoxic glutamate secretion. Inhibiting Src in microglia Rhoa-deficient mice attenuates microglia dysregulation and the ensuing neurological phenotype. We also found that the Rhoa/Src signaling pathway was disrupted in microglia of the APP/PS1 mouse model of Alzheimer’s disease and that low doses of Aß oligomers triggered microglia neurotoxic polarization through the disruption of Rhoa-to-Src signaling. Overall, our results indicate that disturbing RhoGTPase signaling in microglia can directly cause neurodegeneration.

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Amyloid β synaptotoxicity is Wnt‐PCP dependent and blocked by fasudil

Cited by 87 publications

References 49 publications

A role for APP in Wnt signalling links synapse loss with β-amyloid production

A role for APP in Wnt signalling links synapse loss with β-amyloid production

Reducing tau ameliorates behavioural and transcriptional deficits in a novel model of Alzheimer’s disease

Microglia dysfunction caused by the loss of Rhoa disrupts neuronal physiology and leads to neurodegeneration

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