Journal
NEURON
Volume 84, Issue 1, Pages 63-77Publisher
CELL PRESS
DOI: 10.1016/j.neuron.2014.08.048
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Funding
- NIH [R01AG027924, R01AG035355, R01AG046205, P01AG030128, P01NS074969]
- Alzheimer's Association
- Cure Alzheimer's Fund
- Mayo Clinic CRM Career Development Award
- NIRG from the Alzheimer's Association
- GHR Foundation
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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-beta. In humans, LRP6 and Wnt signaling are significantly downregulated in AD brains, likely by a mechanism that depends on amyloid-b. Our results define a critical pathway in which decreased LRP6-mediated Wnt signaling, synaptic dysfunction, and elevated Ab synergistically accelerate AD progression and suggest that restoring LRP6-mediated Wnt signaling can be explored as a viable strategy for AD therapy.
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