TY - JOUR
T1 - Long-term pioglitazone treatment improves learning and attenuates pathological markers in a mouse model of alzheimer's disease
AU - Searcy, James L.
AU - Phelps, Jeremiah T.
AU - Pancani, Tristano
AU - Kadish, Inga
AU - Popovic, Jelena
AU - Anderson, Katie L.
AU - Beckett, Tina L.
AU - Murphy, Michael P.
AU - Chen, Kuey Chu
AU - Blalock, Eric M.
AU - Landfield, Philip W.
AU - Porter, Nada M.
AU - Thibault, Olivier
PY - 2012
Y1 - 2012
N2 - Thiazolidinediones (TZDs) are agonists at peroxisome proliferator-activated gamma-type (PPAR-γ) receptors and are used clinically for the treatment of type 2 diabetes where they have been shown to reestablish insulin sensitivity, improve lipid profiles, and reduce inflammation. Recent work also suggests that TZDs may be beneficial in Alzheimer's disease (AD), ameliorating cognitive decline early in the disease process. However, there have been only a few studies identifying mechanisms through which cognitive benefits may be exerted. Starting at 10 months of age, the triple transgenic mouse model of AD (3xTg-AD) with accelerated amyloid-β (Aβ) deposition and tau pathology was treated with the TZD pioglitazone (PIO-Actos®) at 18 mg/Kg body weight/day. After four months, PIO-treated animals showed multiple beneficial effects, including improved learning on the active avoidance task, reduced serum cholesterol, decreased hippocampal amyloid-β and tau deposits, and enhanced short-and long-term plasticity. Electrophysiological membrane properties and post-treatment blood glucose levels were unchanged by PIO. Gene microarray analyses of hippocampal tissue identified predicted transcriptional responses following TZD treatment as well as potentially novel targets of TZDs, including facilitation of estrogenic processes and decreases in glutamatergic and lipid metabolic/cholesterol dependent processes. Taken together, these results confirm prior animal studies showing that TZDs can ameliorate cognitive deficits associated with AD-related pathology, but also extend these findings by pointing to novel molecular targets in the brain.
AB - Thiazolidinediones (TZDs) are agonists at peroxisome proliferator-activated gamma-type (PPAR-γ) receptors and are used clinically for the treatment of type 2 diabetes where they have been shown to reestablish insulin sensitivity, improve lipid profiles, and reduce inflammation. Recent work also suggests that TZDs may be beneficial in Alzheimer's disease (AD), ameliorating cognitive decline early in the disease process. However, there have been only a few studies identifying mechanisms through which cognitive benefits may be exerted. Starting at 10 months of age, the triple transgenic mouse model of AD (3xTg-AD) with accelerated amyloid-β (Aβ) deposition and tau pathology was treated with the TZD pioglitazone (PIO-Actos®) at 18 mg/Kg body weight/day. After four months, PIO-treated animals showed multiple beneficial effects, including improved learning on the active avoidance task, reduced serum cholesterol, decreased hippocampal amyloid-β and tau deposits, and enhanced short-and long-term plasticity. Electrophysiological membrane properties and post-treatment blood glucose levels were unchanged by PIO. Gene microarray analyses of hippocampal tissue identified predicted transcriptional responses following TZD treatment as well as potentially novel targets of TZDs, including facilitation of estrogenic processes and decreases in glutamatergic and lipid metabolic/cholesterol dependent processes. Taken together, these results confirm prior animal studies showing that TZDs can ameliorate cognitive deficits associated with AD-related pathology, but also extend these findings by pointing to novel molecular targets in the brain.
KW - 3xTg-AD
KW - PPAR
KW - T2DM
KW - aging
KW - hippocampus
KW - long-term potentiation
KW - microarray analysis
KW - pioglitazone
UR - http://www.scopus.com/inward/record.url?scp=84862992514&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84862992514&partnerID=8YFLogxK
U2 - 10.3233/JAD-2012-111661
DO - 10.3233/JAD-2012-111661
M3 - Article
C2 - 22495349
AN - SCOPUS:84862992514
SN - 1387-2877
VL - 30
SP - 943
EP - 961
JO - Journal of Alzheimer's Disease
JF - Journal of Alzheimer's Disease
IS - 4
ER -