Rosiglitazone increases dendritic spine density and rescues spine loss caused by apolipoprotein E4 in primary cortical neurons.
Convergent evidence has revealed an association between insulin resistance and Alzheimer's disease (AD), and the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist, rosiglitazone, an insulin sensitizer and mitochondrial activator, improves cognition in patients with early or mild-to-moderate AD. Apolipoprotein (apo) E4, a major genetic risk factor for AD, exerts neuropathological effects through multiple pathways, including impairment of dendritic spine structure and mitochondrial function. Here we show that rosiglitazone significantly increased dendritic spine density in a dose-dependent manner in cultured primary cortical rat neurons. This effect was abolished by the PPAR-gamma-specific antagonist, GW9662, suggesting that rosiglitazone exerts this effect by activating the PPAR-gamma pathway. Furthermore, the C-terminal-truncated fragment of apoE4 significantly decreased dendritic spine density. Rosiglitazone rescued this detrimental effect. Thus, rosiglitazone might improve cognition in AD patients by increasing dendritic spine density.
Brodbeck
Jens
J
Gladstone Institute of Neurological Disease and Gladstone Institute of Cardiovascular Disease, The J. David Gladstone Institutes, 1650 Owens Street, San Francisco, CA 94158, USA.
Balestra
Maureen E
ME
Saunders
Ann M
AM
Roses
Allen D
AD
Mahley
Robert W
RW
Huang
Yadong
Y
D000818:Animals; D000831:Animals, Newborn; D053327:Apolipoprotein E4 / Q000096:biosynthesis / Q000502:physiology*; D002452:Cell Count; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology* / Q000378:metabolism* / Q000473:pathology; D003712:Dendrites / Q000187:drug effects*; D049229:Dendritic Spines / Q000187:drug effects*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*
D053327:Apolipoprotein E4; D045162:Thiazolidinediones; D000077154:Rosiglitazone