Rosiglitazone increases dendritic spine density and rescues spine loss caused by apolipoprotein E4 in primary cortical neurons

Gladstone Institute of Neurological Disease and Gladstone Institute of Cardiovascular Disease, The J. David Gladstone Institutes, 1650 Owens Street, San Francisco, CA 94158, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 02/2008; 105(4):1343-6. DOI: 10.1073/pnas.0709906104
Source: PubMed


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.

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    • "These PPARγ agonists inhibit inflammatory gene expression, alter Amyloid homeostasis & exhibit neuroprotective effects. Initial research suggests intranasal insulin might also be utilized -increasing insulin levels in the brain with minimal insulin increase in the rest of the body: Afrezza, a New Inhaled Insulin, Is Approved by the F.D.A.[52] Allopregnanolone is a hormone recently shown to promote neurogenesis that reverses cognitive deficits, reduce brain pathology, and improve cognition in Alzheimer's model mice. Its levels decline in the brain in old age and AD.[53] [54] "

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    • "In this context, Brodbeck et al. studied the effects of rosiglitazone on dendritic spine density in AD mice that expressed Apo-E4 [64]. Treatment with rosiglitazone significantly increased dendritic spine density in a dose-dependent manner in cultured cortical neurons from wild type mice [64]. This effect was prevented by GW9662, suggesting that rosiglitazone exerts this effect by activating the PPARγ [64]. "
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    • "Consistent with the role of soluble A␤ 42 oligomers and rosiglitazone in filopodium density, A␤ 42 oligomers also reduced spine and synapse densities and rosiglitazone pre-treatment prevented soluble A␤ 42 oligomer-induced spine and synapse loss in a dose-dependent manner. Previous study has demonstrated that rosiglitazone rescues the apolipoprotein E4-mediated spine loss in primary cortical neurons [32]. Our result suggested that rosiglitazone also has a neuroprotective effect on the soluble A␤ 42 oligomerinduced loss of synapses in AD. "
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    ABSTRACT: Rosiglitazone has been known to attenuate neurodegeneration in Alzheimer's disease (AD), but the underlying mechanisms remain to be fully elucidated. In this study, living-cell image, immunocytochemistry, and electrophysiology were used to examine the effects of soluble amyloid-β protein (Aβ) oligomers and rosiglitazone on the synapse formation, plasticity, and mitochondrial distribution in cultured neurons. Incubation of hippocampal cultures with amyloid-β (Aβ)42 oligomers (0.5 μM) for 3 h significantly decreased dendritic filopodium and synapse density. Pretreatment with rosiglitazone (0.5-5 μM) for 24 h prevented the Aβ42-induced loss of dendritic filopodium and synapse in a dose-dependent manner. However, neither Aβ42 oligomer nor rosiglitazone has a significant effect on the velocity and length of dendritic filopodia. Electrophysiological recording showed that acute exposure of slices with 0.5 μM Aβ42 oligomers impaired hippocampal long-term potentiation (LTP). Pre-incubation of hippocampal slices with rosiglitazone significantly prevented the Aβ42-induced LTP deficit, which depended on rosiglitazone concentrations (1-5 μM) and pretreatment period (1-5 h). The beneficial effects of rosiglitazone were abolished by the peroxisome proliferator-activated receptor gamma (PPARγ) specific antagonist, GW9662. Moreover, the mitochondrial numbers in the dendrite and spine were decreased by Aβ42 oligomers, which can be prevented by rosiglitazone. In conclusion, our data suggested that rosiglitazone prevents Aβ42 oligomers-induced impairment via increasing mitochondrial numbers in the dendrite and spine, improving synapse formation and plasticity. This process is most likely through the PPARγ-dependent pathway and in concentration and time dependent manners. The study provides novel insights into the mechanisms for the protective effects of rosiglitzone on AD.
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