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

ABSTRACT: 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 (APP_Swe) 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.

SUBMITTER: Elliott C

PROVIDER: S-EPMC6145937 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The accumulation of amyloid-β (Aβ) plays a pivotal early event in the pathogenesis of Alzheimer's disease (AD). In the brain, neurons produce Aβ by the proteolytic processing of amyloid precursor protein (APP) through the endocytic pathway, whereas microglia mediate Aβ clearance also via endocytic mechanisms. Previous studies have shown the critical importance of cofilin, a filamentous actin-severing protein, in actin dynamics and pathogen-triggered endocytic processes. Moreover, the binding of Aβ42 oligomers to β1-integrin triggers the cofilin activation, and in turn, cofilin promotes the internalization of surface β1-integrin. However, a role for cofilin in APP processing and Aβ metabolism has not been investigated. In this study, we found that knockdown of cofilin in Chinese hamster ovary 7WD10 cells and primary neurons significantly reduces Aβ production by increasing surface APP (sAPP) levels. Expression of active (S3A) but not inactive (S3E) cofilin reduces sAPP levels by enhancing APP endocytosis. Accordingly, Aβ deposition in APP and presenilin 1 (PS1) transgenic mice is significantly reduced by genetic reduction of cofilin (APP/PS1;cofilin+/-). However, the reduction of Aβ load in APP/PS1;cofilin+/- mice is paradoxically associated with significantly increased ionized calcium-binding adaptor molecule 1-positive microglial activation surrounding Aβ deposits. Primary microglia isolated from cofilin+/- mice demonstrate significantly enhanced state of activation and greater ability to uptake and clear Aβ42, which is reversed with the active (S3A) but not inactive (S3E) form of cofilin. These results taken together indicate a significant role for cofilin in Aβ accumulation via dual and opposing endocytic mechanisms of promoting Aβ production in neurons and inhibiting Aβ clearance in microglia.-Liu, T., Woo, J.-A. A., Yan, Y., LePochat, P., Bukhari, M. Z., Kang, D. E. Dual role of cofilin in APP trafficking and amyloid-β clearance.

Project description:Characteristic features of Alzheimer's disease are memory loss, plaques resulting from abnormal processing of amyloid precursor protein (APP), and presence of neurofibrillary tangles and dystrophic neurites containing hyperphosphorylated tau. Currently, it is not known what links these abnormalities together. Cytoplasmic FMR1 interacting protein 2 (CYFIP2) has been suggested to regulate mRNA translation at synapses and this may include local synthesis of APP and alpha-calcium/calmodulin-dependent kinase II, a kinase that can phosphorylate tau. Further, CYFIP2 is part of the Wiskott-Aldrich syndrome protein-family verprolin-homologous protein complex, which has been implicated in actin polymerization at synapses, a process thought to be required for memory formation. Our previous studies on p25 dysregulation put forward the hypothesis that CYFIP2 expression is reduced in Alzheimer's disease and that this contributes to memory impairment, abnormal APP processing and tau hyperphosphorylation. Here, we tested this hypothesis. First, in post-mortem tissue CYFIP2 expression was reduced by ?50% in severe Alzheimer's hippocampus and superior temporal gyrus when normalized to expression of a neuronal or synaptic marker protein. Interestingly, there was also a trend for decreased expression in mild Alzheimer's disease hippocampus. Second, CYFIP2 expression was reduced in old but not in young Tg2576 mice, a model of familial Alzheimer's disease. Finally, we tested the direct impact of reduced CYFIP2 expression in heterozygous null mutant mice. We found that in hippocampus this reduced expression causes an increase in APP and ?-site amyloid precursor protein cleaving enzyme 1 (BACE1) protein, but not mRNA expression, and elevates production of amyloid-?42 Reduced CYFIP2 expression also increases alpha-calcium/calmodulin-dependent kinase II protein expression, and this is associated with hyperphosphorylation of tau at serine-214. The reduced expression also impairs spine maturity without affecting spine density in apical dendrites of CA1 pyramidal neurons. Furthermore, the reduced expression prevents retention of spatial memory in the water maze. Taken together, our findings indicate that reduced CYFIP2 expression triggers a cascade of change towards Alzheimer's disease, including amyloid production, tau hyperphosphorylation and memory loss. We therefore suggest that CYFIP2 could be a potential hub for targeting treatment of the disease.

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

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