Cerebral Wnt and Insulin Signaling

LRP6-mediated Wnt signaling, synaptic function and amyloid pathogenesis

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. Despite these implications, the molecular mechanism by which LRP6 regulates AD pathogenesis is poorly understood. Using a myriad of techniques, including cell biology and animal models, the lab has demonstrated that impairment of the Wnt and LRP6 pathway elevated abeta production and exacerbated amyloidogenesis. In addition, this pathway plays an essential role in regulating synaptic integrity and functions even in the absence of amyloid pathology.

LRP1 regulation of brain insulin signaling and glucose metabolism

Type 2 diabetes mellitus, a metabolic disorder characterized by insulin resistance and glucose intolerance, significantly increases the risk of developing AD. Whereas abeta deposition and neurofibrillary tangles are major histological hallmarks of AD, impairment of cerebral glucose metabolism precedes these pathological changes during the early stage of AD and likely triggers or exacerbates AD pathology.

However, the mechanisms linking dysregulated insulin signaling with glucose metabolism and AD pathogenesis remain unclear. LRP1 plays critical roles in lipoprotein metabolism, synaptic maintenance and clearance of abeta in the brain. Dr. Bu's lab has further demonstrated that LRP1 interacts with the insulin receptor beta subunit in the brain and regulates insulin signaling and glucose uptake. LRP1 deficiency in neurons leads to impaired insulin signaling as well as reduced levels of glucose transporters, and consequently, glucose uptake is reduced. Using an innovative technique to sample brain glucose concentrations in freely moving mice, the lab observed that LRP1 deficiency in conditional knockout mice resulted in glucose intolerance in the brain. Interestingly, hyperglycemia suppresses LRP1 expression, which further exacerbates insulin resistance, glucose intolerance and AD pathology. Since a loss of LRP1 expression is seen in AD brains, this pivotal study provides novel insights into insulin resistance in AD.