Publication

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 coreceptor 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 downregulated 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 viable strategy for AD therapy. 

Publication

There are more than 70,000 Oklahomans who suffer from Alzheimer's disease (AD) and it is estimated that 96,000 patients will be diagnosed with AD by 2025 in Oklahoma. Cognitive decline in Alzheimer's disease is thought to be the result of disturbed neuronal communication due to synaptic dysfunction. Aggregated amyloid beta protein accumulates in AD, a process dependent on synaptic activity. In this series of studies we investigate how synaptobrevin1, an essential synaptic protein, regulates amyloid secretion. Maintaining physiological synaptic function while reducing amyloid secretion may provide a breakthrough to design effective therapies that halt progression of dementia in Alzheimer's disease.