title: Abnormal thiamine-dependent processes in Alzheimer's Disease. Lessons from diabetes.
abstract: Reduced glucose metabolism is an invariant feature of Alzheimer's Disease (AD) and an outstanding biomarker of disease progression. Glucose metabolism may be an attractive therapeutic target, whether the decline initiates AD pathophysiology or is a critical component of a cascade. The cause of cerebral regional glucose hypometabolism remains unclear. Thiamine-dependent processes are critical in glucose metabolism and are diminished in brains of AD patients at autopsy. Further, the reductions in thiamine-dependent processes are highly correlated to the decline in clinical dementia rating scales. In animal models, thiamine deficiency exacerbates plaque formation, promotes phosphorylation of tau and impairs memory. In contrast, treatment of mouse models of AD with the thiamine derivative benfotiamine diminishes plaques, decreases phosphorylation of tau and reverses memory deficits. Diabetes predisposes to AD, which suggests they may share some common mechanisms. Benfotiamine diminishes peripheral neuropathy in diabetic humans and animals. In diabetes, benfotiamine induces key thiamine-dependent enzymes of the pentose shunt to reduce accumulation of toxic metabolites including advanced glycation end products (AGE). Related mechanisms may lead to reversal of plaque formation by benfotiamine in animals. If so, the use of benfotiamine could provide a safe intervention to reverse biological and clinical processes of AD progression. This article is part of a Special Issue entitled 'Mitochondrial function and dysfunction in neurodegeneration'.
authors.affiliation: Department of Neurology and Neuroscience, Weill Cornell Medical College, Burke Medical Research Institute, 785 Mamaroneck Avenue, White Plains, NY 10605, USA. ggibson@med.cornell.edu
authors.forename: Gary E
authors.initials: GE
authors.lastname: Gibson
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Hirsch
authors.forename: Rosanna T
authors.initials: RT
authors.lastname: Cirio
authors.forename: Barry D
authors.initials: BD
authors.lastname: Jordan
authors.forename: Pasquale
authors.initials: P
authors.lastname: Fonzetti
authors.forename: Jessica
authors.initials: J
authors.lastname: Elder
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D044882:Glucose Metabolism Disorders / Q000378:metabolism*; D006801:Humans; D013831:Thiamine / Q000378:metabolism*
chemical_list: D005947:Glucose; D013831:Thiamine