Deficiency in LRP6-Mediated Wnt Signaling Contributes to Synaptic Abnormalities and Amyloid Pathology in Alzheimer’s Disease

Abstract

SUMMARY Alzheimer’s disease (AD) is an age-related neurological disorder characterized by synaptic loss and dementia. The low-density lipoprotein receptor-related protein 6 (LRP6) is an essential co-receptor for Wnt signaling and its genetic variants have been linked to AD risk. Here we report that neuronal LRP6-mediated Wnt signaling is critical for synaptic function and cognition. Conditional deletion of Lrp6 gene in mouse forebrain neurons leads to age-dependent deficits in synaptic integrity and memory. Neuronal LRP6 deficiency in an amyloid mouse model also leads to exacerbated amyloid pathology due to increased APP processing to amyloid-β. In humans, LRP6 and Wnt signaling are significantly down-regulated in AD brains, likely by a mechanism that depends on amyloid-β. Our results define a critical pathway in which decreased LRP6-mediated Wnt signaling, synaptic dysfunction and elevated Aβ synergistically accelerate AD progression, and suggest that restoring LRP6-mediated Wnt signaling can be explored as a novel strategy for AD therapy.

Wnt5a is essential for hippocampal dendritic maintenance and spatial learning and memory in adult mice

“…Previously, broad-spectrum Wnt antagonists have been shown to affect synaptic structure, plasticity, and cognitive functions in adult organisms (37)(38)(39)(40)(41). However, there are 19 vertebrate Wnts, and which Wnt is essential for these functions in the adult brain in vivo remains unknown.…”

Harnessing low-density lipoprotein receptor protein 6 (LRP6) genetic variation and Wnt signaling for innovative diagnostics in complex diseases

“…62 This study showed that neuronal LRP6 deficiency contributed to significant memory impairment, impaired long-term potentiation induction, correlating with learning and memory, and increased expression of glial fibrillary acidic protein and ionized calcium-binding adaptor molecule 1 (Iba1), markers for astrocyte and microglia activation, respectively. 62 Furthermore, the study reported that LRP6 deficiency significantly increased mouse endogenous Aβ40 and Aβ42 levels in the brain compared with control mice. 62 Despite evidence demonstrating the relevance between LRP6 and Aβ levels, the researchers designed in vitro experiments in human neuroblastoma SH-SY5Y cells overexpressing human APP (SHSY5Y-APP) to confirm the in vivo results.…”

“…They found that LRP6 regulated APP trafficking and processing to Aβ 62 and also reported that LRP6 levels and Wnt signaling were down-regulated in AD brains in comparison with controls. 62 All these studies showed that LRP6 deficiency contributed to the development of AD.…”

“…62 Furthermore, the study reported that LRP6 deficiency significantly increased mouse endogenous Aβ40 and Aβ42 levels in the brain compared with control mice. 62 Despite evidence demonstrating the relevance between LRP6 and Aβ levels, the researchers designed in vitro experiments in human neuroblastoma SH-SY5Y cells overexpressing human APP (SHSY5Y-APP) to confirm the in vivo results. They found that LRP6 regulated APP trafficking and processing to Aβ 62 and also reported that LRP6 levels and Wnt signaling were down-regulated in AD brains in comparison with controls.…”

“…62 Despite evidence demonstrating the relevance between LRP6 and Aβ levels, the researchers designed in vitro experiments in human neuroblastoma SH-SY5Y cells overexpressing human APP (SHSY5Y-APP) to confirm the in vivo results. They found that LRP6 regulated APP trafficking and processing to Aβ 62 and also reported that LRP6 levels and Wnt signaling were down-regulated in AD brains in comparison with controls. 62 All these studies showed that LRP6 deficiency contributed to the development of AD.…”