title: Insulin sensitizers improve learning and attenuate tau hyperphosphorylation and neuroinflammation in 3xTg-AD mice.
abstract: Sporadic Alzheimer's disease (AD) is a multifactorial metabolic brain disorder characterized by progressive neurodegeneration. Decreased brain energy and glucose metabolism occurs before the appearance of AD symptoms and worsens while the disease progresses. Deregulated brain insulin signaling has also been found in AD recently. To restore brain insulin sensitivity and glucose metabolism, pioglitazone and rosiglitazone, two insulin sensitizers commonly used for treating type 2 diabetes, have been studied and shown to have some beneficial effects in AD mouse models. However, the molecular mechanisms of the beneficial effects remain elusive. In the present study, we treated the 3xTg-AD mice, a widely used mouse model of AD, with pioglitazone and rosiglitazone for 4 months and studied the effects of the treatments on cognitive performance and AD-related brain alterations. We found that the chronic treatment improved spatial learning, enhanced AKT signaling, and attenuated tau hyperphosphorylation and neuroinflammation. These findings shed new light on the possible mechanisms by which these two insulin sensitizers might be useful for treating AD and support further clinical trials evaluating the efficacy of these drugs.
authors.affiliation: Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY, 10314-6399, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Li
authors.forename: Julie
authors.initials: J
authors.lastname: Blanchard
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Khalid
authors.initials: K
authors.lastname: Iqbal
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.forename: Cheng-Xin
authors.initials: CX
authors.lastname: Gong
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007859:Learning Disabilities / Q000188:drug therapy* / Q000503:physiopathology; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology; D018697:Nootropic Agents / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D000077205:Pioglitazone; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000077154:Rosiglitazone; D065853:Spatial Learning / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D007004:Hypoglycemic Agents; C558298:Mapt protein, mouse; D018696:Neuroprotective Agents; D018697:Nootropic Agents; D045162:Thiazolidinediones; D016875:tau Proteins; D000077154:Rosiglitazone; D051057:Proto-Oncogene Proteins c-akt; D000077205:Pioglitazone
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