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: 9.81). 02/2008; 105(4):1343-6. DOI: 10.1073/pnas.0709906104
Source: PubMed

ABSTRACT 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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Available from: Allen D Roses, Aug 15, 2015
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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.
    Journal of Alzheimer's disease: JAD 10/2013; 39(2). DOI:10.3233/JAD-130680 · 4.15 Impact Factor
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    • "Therefore, some investigators have proposed the term, T3DM or brain insulin resistance, to reflect the dysfunction of insulin signaling pathway in AD (de la Monte and Wands, 2008; Steen et al., 2005). Insulinsensitizing agents such as ligands for g-peroxisome proliferatoractived receptor (g-PPAR) and intranasal insulin have offered a potential therapeutic solution (Brodbeck et al., 2008; Reger et al., 2008a,b). The study by Zhao et al. (2008a,b) showed that neuronal insulin signal transduction was prone to be disrupted by soluble Ab oligomers, which caused a rapid and substantial loss of dendritic IRs through redistribution of the receptors, suggesting that soluble Ab oligomers are responsible for insulin resistance and synaptic dysfunction in AD brain. "
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    ABSTRACT: Alzheimer's disease (AD) is an age-related devastating neurodegenerative disorder, which severely impacts on the global economic development and healthcare system. Though AD has been studied for more than 100 years since 1906, the exact cause(s) and pathogenic mechanism(s) remain to be clarified. Also, the efficient disease- modifying treatment and ideal diagnostic method for AD are unavailable. Perturbed cerebral glucose metabolism, an invariant pathophysiological feature of AD, may be a critical contributor to the pathogenesis of this disease. In this review, we firstly discussed the features of cerebral glucose metabolism in physiological and pathological conditions. Then, we further reviewed the contribution of glucose transportation abnormality and intracellular glucose catabolism dysfunction in AD pathophysiology, and proposed a hypothesis that multiple pathogenic cascades induced by impaired cerebral glucose metabolism could result in neuronal degeneration and consequently cognitive deficits in AD patients. Among these pathogenic processes, altered functional status of thiamine metabolism and brain insulin resistance are highly emphasized and characterized as major pathogenic mechanisms. Finally, considering the fact that AD patients exhibit cerebral glucose hypometabolism possibly due to impairments of insulin signaling and altered thiamine metabolism, we also discuss some potential possibilities to uncover diagnostic biomarkers for AD from abnormal glucose metabolism and to develop drugs targeting at repairing insulin signaling impairment and correcting thiamine metabolism abnormality. We conclude that glucose metabolism abnormality plays a critical role in AD pathophysiological alterations through the induction of multiple pathogenic factors such as oxidative stress, mitochondrial dysfunction, and so forth. To clarify the causes, pathogeneses and consequences of cerebral hypometabolism in AD will help break the bottleneck of current AD study in finding ideal diagnostic biomarker and disease-modifying therapy.
    Progress in Neurobiology 07/2013; 108. DOI:10.1016/j.pneurobio.2013.06.004 · 10.30 Impact Factor
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    • "04 ) , transgenic mice models of AD ( Pedersen and Flynn , 2004 ; Pedersen et al . , 2006 ) and obesity models ( Kramer et al . , 2001 ) . Dendritic spine density is increased in a dose - dependent manner when incubated for 24 hours with ROSI and is prevented by PPAR␥ - specific antagonist , suggesting that this modulation involves PPAR␥ pathway ( Brodbeck et al . , 2008 ) . Additionally , certain molecular changes are ob - served with ROSI administration in rats , such as upregula - tion of glucose transporter protein ( GLUT1 and 4 ) ( Kramer et al . , 2001 ; Young et al . , 1995 ) . Neurophysiologically , deficits in learning and memory and in synaptic plasticity ( specifically long - term potentiatio"
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    ABSTRACT: As an antidiabetic agent, rosiglitazone (ROSI) binds and activates peroxisome proliferator-activator receptor gamma (PPARγ), altering the expression of genes involved in glucose uptake and disposal, ultimately affecting glucose regulation. ROSI might therefore be a potential treatment to ameliorate age-related decline in cognitive function, particularly on an insulin-resistant background, where improvements in peripheral insulin sensitivity and central nervous system (CNS) glucose utilization may facilitate recovery of cognitive function. We therefore examined the amelioration potential of ROSI for neurocognitive deficits resulting from aging in an animal model. Behaviorally, acute and chronic ROSI treatments enhanced acquisition of learning in the water plus maze, a modified version of the Morris water maze task. In parallel, restoration of synaptic plasticity in the dentate gyrus of ROSI-treated middle-aged rats was evident after a single dose intake. Additionally, the spatial receptive fields of hippocampal CA1 place cells were significantly improved by chronic ROSI administration. ROSI treatment reversed basal plasma insulin abnormalities and increased hippocampal glucose transporter (GLUT)-3 expression in middle-aged rats. Taken together, these results suggest that ROSI modulates hippocampal circuitry effectively to promote an improvement in cognitive function, possibly via a glucose transporter-3 mechanism.
    Neurobiology of aging 04/2012; 33(4):835.e13-30. DOI:10.1016/j.neurobiolaging.2011.08.013 · 4.85 Impact Factor
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