Rejuvenating Neurons: Signaling Pathways

Signaling pathways regulate numerous cellular processes including cellular survival. Dr. Bu's Neurobiology of Alzheimer's Disease Lab at Mayo Clinic is studying signaling pathway restoration to develop new treatments for Alzheimer's disease (AD). Dr. Bu's research team is also uncovering the effects of apoE and apoE receptors on brain insulin signaling and glucose metabolism.

Wnt/β-catenin signaling in neuronal survival, synaptic function and Alzheimer's disease pathogenesis

Wnt/β-catenin signaling is an essential pathway that regulates numerous cellular processes including cellular survival. In the brain, Wnt/β-catenin signaling not only is critical for neuronal survival but also plays an important role in regulating synaptic plasticity. Moreover, Wnt/β-catenin signaling is required for blood-brain barrier (BBB) formation and maintenance and can inhibit the amyloid-beta (Aβ) production and tau protein hyperphosphorylation. Wnt/β-catenin signaling is greatly suppressed in people who have AD. As such, restoring Wnt/β-catenin signaling represents a unique opportunity for rational AD therapy.

The low-density lipoprotein receptor-related protein 6 (LRP6) is an essential Wnt coreceptor for Wnt/β-catenin 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, Dr. Bu's lab has demonstrated that impairment of the Wnt and LRP6-mediated Wnt/β-catenin signaling elevated Aβ production and exacerbated amyloidogenesis. Moreover, the lab is developing small molecule Wnt activators for AD therapy.

The effects of apoE and apoE receptors on 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 Alzheimer's disease (AD). Aβ deposition and neurofibrillary tangles are major histological hallmarks of AD; impairment of cerebral glucose metabolism precedes these pathological changes during the early stages of AD and likely triggers or exacerbates AD pathology. However, the mechanisms linking dysregulated insulin signaling with glucose metabolism and AD pathogenesis remain unclear.

The low-density lipoprotein receptor-related protein 1 (LRP1) is a major receptor for both apoE and Aβ and plays essential roles in brain Aβ clearance. LRP1 expression is downregulated in the brain of a person with AD. Dr. Bu's lab has demonstrated that LRP1 interacts with the insulin receptor beta subunit in the brain and regulates insulin signaling and glucose uptake. Critically, LRP1 deficiency in neurons leads to impaired insulin signaling as well as reduced levels of glucose transporters and, consequently, glucose uptake is reduced.

The association between diabetes and AD-associated amyloid pathology is stronger among carriers of the APOE4 gene, the strongest genetic risk factor for late-onset AD. Fluorodeoxyglucose (FDG)-positron emission tomography (PET) studies showed that APOE4 carriers, either as healthy adults or with dementia, have lower cerebral glucose metabolism. Recent clinical trials have also revealed that the beneficial effects of intranasal insulin treatment on cognitive improvement in patients with AD are modulated by APOE genotype status.

The Neurobiology of Alzheimer's Disease Lab found that apoE4 impairs neuronal insulin signaling in human apoE-targeted replacement mice in an age-dependent manner. A high-fat diet (HFD) accelerates these effects in apoE4 mice at middle age. In primary neurons, apoE4 interacts with insulin receptors and impairs trafficking by trapping insulin in the endosomes, leading to impaired insulin signaling and insulin-stimulated mitochondrial respiration and glycolysis. In aging brains, the increased apoE4 aggregation and compromised endosomal function further exacerbate the inhibitory effects of apoE4 on insulin signaling and related functions. Together, these findings provide novel mechanistic insights into the pathogenic mechanisms of insulin resistance associated with LRP1 and apoE4 in AD.

Key Publications

Zhao N, Liu CC, Van Ingelgom AJ, Martens YA, Linares C, Knight JA, Painter MM, Sullivan PM, Bu G. Apolipoprotein E4 impairs neuronal insulin signaling by trapping insulin receptor in the endosomes. Neuron. 2017; doi:10.1016/j.neuron.2017.09.003