Protecting synapses from amyloid β-associated degeneration by manipulations of Wnt/planar cell polarity signaling

Abstract

Synapse loss is an early event in Alzheimer’s disease and is thought to be associated with amyloid pathology and caused by Amyloid β (Aβ) oligomers. Whether and how Aβ oligomers directly target signaling pathways for glutamatergic synapse maintenance is unknown. Glutamatergic synapse development is controlled by the opposing functions of Celsr3 and Vangl2, core components of the Wnt/planar cell polarity (PCP) signaling pathway, functioning directly in the synapses. Celsr3 promotes synapse formation, whereas Vangl2 inhibits synapse formation. Here we show that oligomeric Aβ binds to Celsr3 and assists Vangl2 in disassembling synapses by disrupting the intercellular Celsr3/Frizzled3-Celsr3 complex, essential for PCP signaling. Together with Vangl2, a Wnt receptor, Ryk, is also required for Aβ oligomer-induced synapse loss in a mouse model of Alzheimer’s disease, 5XFAD, where conditional Ryk knockout protected synapses and preserved cognitive function. Our study reveals a fine balance of Wnt/PCP signaling components in glutamatergic synapse maintenance and suggests that overproduced Aβ oligomers may lead to excessive synapse loss by tipping this balance. Together with previous reports that an inhibitor of Wnt/Ryk signaling, WIF1, is found reduced in Alzheimer’s disease patients, our results suggest that the imbalance of PCP signaling in these patients may contribute to synapse loss in Alzheimer’s disease and manipulating Wnt/PCP signaling may preserve synapses and cognitive function.

Neurons and Astrocytes Elicit Brain Region Specific Transcriptional Responses to Prion Disease in the Murine CA1 and Thalamus

“…Another transcript of note that was increased was Ceslr3 , recently reported to encode a key protein involved in synapse stability (Thakar et al, 2017 ). This protein has been linked to loss of synapses in Alzheimer's disease in a pre-print paper (Feng et al, 2020 ) and increased transcription may be a feedback response to synapse degeneration.…”

Genotype by environment interactions for chronic wasting disease in farmed US white-tailed deer

“…Nevertheless, it should also be noted that EMMAX is known to produce conservative P -values ( Zhou and Stephens 2012 ). In addition to PRNP , an investigation of nominally significant SNPs ( P -value ≤ 5E-05) revealed positional candidate genes previously implicated in aspects of prion disease ( TPH2 ; PDE4DIP ), including scrapie ( ACSL4 ), regulation of the central nervous system ( ADGRB3 ), neuroprotection ( EN1 ), Alzheimer’s ( ASCL1 , AMOTL2 , RYK ), and Parkinson’s disease ( EN1 , ASCL1 , RTL9 ) ( Ide et al 2005 ; Roffé et al 2010 ; Filali et al 2014 ; Nishizawa et al 2014 ; Alleaume-Butaux et al 2015 ; Rekaik et al 2015 ; Dunn et al 2019 ; Meyer et al 2019 ; Scuderi et al 2019 ; Feng et al 2020 ; Gallart-Palau et al 2020 ; Le Guen et al 2020 ). Additional missense variants encoded by PRNP codons 37, 95, and 226 did not meet the nominal significance level ( P -value ≤ 5E-05) for polygenic traits ( Wellcome Trust Case Control Consortium 2007 ; Neibergs et al 2014 ; Seabury et al 2017 , 2020 ).…”