title: Neuronal LRP1 regulates glucose metabolism and insulin signaling in the brain.
abstract: Alzheimer's disease (AD) is a neurological disorder characterized by profound memory loss and progressive dementia. Accumulating evidence suggests that Type 2 diabetes mellitus, a metabolic disorder characterized by insulin resistance and glucose intolerance, significantly increases the risk for developing AD. Whereas amyloid-β (Aβ) 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 disturbed insulin signaling/glucose metabolism and AD pathogenesis remain unclear. The low-density lipoprotein receptor-related protein 1 (LRP1), a major apolipoprotein E receptor, plays critical roles in lipoprotein metabolism, synaptic maintenance, and clearance of Aβ in the brain. Here, we demonstrate that LRP1 interacts with the insulin receptor β 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 GLUT3 and GLUT4. Consequently, glucose uptake is reduced. By using an in vivo microdialysis technique sampling brain glucose concentration in freely moving mice, we further show that LRP1 deficiency in conditional knock-out mice resulted in glucose intolerance in the brain. We also found that hyperglycemia suppresses LRP1 expression, which further exacerbates insulin resistance, glucose intolerance, and AD pathology. As loss of LRP1 expression is seen in AD brains, our study provides novel insights into insulin resistance in AD. Our work also establishes new targets that can be explored for AD prevention or therapy.
authors: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, and Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian 361005, China.
authors: Chia-Chen
authors: CC
authors: Liu
authors: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, and Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian 361005, China.
authors: Jin
authors: J
authors: Hu
authors: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, and.
authors: Chih-Wei
authors: CW
authors: Tsai
authors: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, and.
authors: Mei
authors: M
authors: Yue
authors: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, and.
authors: Heather L
authors: HL
authors: Melrose
authors: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, and.
authors: Takahisa
authors: T
authors: Kanekiyo
authors: Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, and Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, Fujian 361005, China bu.guojun@mayo.edu.
authors: Guojun
authors: G
authors: Bu
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000503:physiopathology; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002461:Cell Line, Transformed; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000473:pathology*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005947:Glucose / Q000378:metabolism*; D018149:Glucose Intolerance / Q000235:genetics; D051274:Glucose Transporter Type 3 / Q000235:genetics / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D021381:Protein Transport / Q000235:genetics; D034622:RNA Interference / Q000502:physiology; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000235:genetics
chemical_list: D051274:Glucose Transporter Type 3; D051275:Glucose Transporter Type 4; D007328:Insulin; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D011973:Receptors, LDL; C495689:Slc2a3 protein, mouse; C495693:Slc2a4 protein, mouse; D025521:Tumor Suppressor Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D005947:Glucose
keywords: Alzheimer's disease; LRP1; apolipoprotein E; glucose metabolism; insulin signaling