Hyperleucinemia causes hippocampal retromer deficiency linking diabetes to Alzheimer's disease.
Type 2 diabetes (T2D) is a major risk factor for late-onset Alzheimer's disease (AD). A variety of metabolic changes related to T2D (e.g. hyperinsulinemia, hyperglycemia, and elevated branched-chain amino acids) have been proposed as mechanistic links, but the basis for this association remains unknown. Retromer-dependent trafficking is implicated in the pathogenesis of AD, and two key retromer proteins, VPS35 and VPS26, are deficient in the hippocampal formation of AD patients. We characterized VPS35 levels in five different mouse models of T2D/obesity to identify specific metabolic factors that could affect retromer levels in the brain. Mouse models in which hyperleucinemia was present displayed hippocampus-selective retromer deficiency. Wild-type lean mice fed a high leucine diet also developed hippocampal-selective retromer deficiency, and neuronal-like cells grown in high ambient leucine had reduced retromer complex proteins. Our results suggest that hyperleucinemia may account, in part, for the association of insulin resistance/T2D with AD.
Naomi Berrie Diabetes Center, Division of Molecular Genetics, Department of Pediatrics, College of Physicians & Surgeons, New York, NY, USA.
Michael V
MV
Morabito
The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians & Surgeons, New York, NY, USA; Department of Pathology and Cell Biology, College of Physicians & Surgeons, New York, NY, USA.
Diego E
DE
Berman
The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians & Surgeons, New York, NY, USA.
Remy T
RT
Schneider
Naomi Berrie Diabetes Center, Division of Molecular Genetics, Department of Pediatrics, College of Physicians & Surgeons, New York, NY, USA.
Yiying
Y
Zhang
Naomi Berrie Diabetes Center, Division of Molecular Genetics, Department of Pediatrics, College of Physicians & Surgeons, New York, NY, USA.
Rudolph L
RL
Leibel
The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians & Surgeons, New York, NY, USA; Department of Neurology, Columbia University, College of Physicians & Surgeons, New York, NY, USA. Electronic address: sas68@columbia.edu.
Scott A
SA
Small
D000544:Alzheimer Disease / Q000209:etiology* / Q000473:pathology*; D000704:Analysis of Variance; D000818:Animals; D045744:Cell Line, Tumor; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000235:genetics; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005951:Glucose Tolerance Test; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D020738:Leptin / Q000235:genetics; D007930:Leucine / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009447:Neuroblastoma / Q000473:pathology; D033921:Vesicular Transport Proteins / Q000172:deficiency* / Q000235:genetics
D020738:Leptin; C498296:VPS26A protein, human; C419573:VPS35 protein, human; D033921:Vesicular Transport Proteins; D007930:Leucine
Alzheimer's disease; Diabetes; Obesity; Retromer