Central activation of PPAR-gamma ameliorates diabetes induced cognitive dysfunction and improves BDNF expression

Kariharan, Thiruchelvam; Nanayakkara, Gayani; Parameshwaran, Kodeeswaran; Bagasrawala, Inseyah; Ahuja, Manuj; Abdel‐Rahman, Engy A.; Amin, Arin T.; Dhanasekaran, Murali; Suppiramaniam, Vishnu; Amin, Rajesh

doi:10.1016/j.neurobiolaging.2014.09.028

Cited by 94 publications

(78 citation statements)

References 57 publications

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“…In line with our findings was the report showing that exerciseinduced BDNF expression was mediated by PGC-1α regulation of Fndc5 gene expression (20). Moreover, PPARγ and PPARα, the main transcription factors regulated by PGC-1α, induced the transcription of BDNF in cultured neurons and glial cells (21,22). Combined, these data are fully consistent with a mechanism for the neuroprotective effects of hPGC-1α in APP23 mice mediated, at least partially, by increased transcription of specific growth factors (Fig.…”

Section: Discussionsupporting

confidence: 92%

PPARγ-coactivator-1α gene transfer reduces neuronal loss and amyloid-β generation by reducing β-secretase in an Alzheimer’s disease model

Katsouri

Lim

Blondrath

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

123

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Current therapies for Alzheimer's disease (AD) are symptomatic and do not target the underlying Aβ pathology and other important hallmarks including neuronal loss. PPARγ-coactivator-1α (PGC-1α) is a cofactor for transcription factors including the peroxisome proliferator-activated receptor-γ (PPARγ), and it is involved in the regulation of metabolic genes, oxidative phosphorylation, and mitochondrial biogenesis. We previously reported that PGC-1α also regulates the transcription of β-APP cleaving enzyme (BACE1), the main enzyme involved in Aβ generation, and its expression is decreased in AD patients. We aimed to explore the potential therapeutic effect of PGC-1α by generating a lentiviral vector to express human PGC-1α and target it by stereotaxic delivery to hippocampus and cortex of APP23 transgenic mice at the preclinical stage of the disease. Four months after injection, APP23 mice treated with hPGC-1α showed improved spatial and recognition memory concomitant with a significant reduction in Aβ deposition, associated with a decrease in BACE1 expression. hPGC-1α overexpression attenuated the levels of proinflammatory cytokines and microglial activation. This effect was accompanied by a marked preservation of pyramidal neurons in the CA3 area and increased expression of neurotrophic factors. The neuroprotective effects were secondary to a reduction in Aβ pathology and neuroinflammation, because wild-type mice receiving the same treatment were unaffected. These results suggest that the selective induction of PGC-1α gene in specific areas of the brain is effective in targeting AD-related neurodegeneration and holds potential as therapeutic intervention for this disease.Aβ | BACE1 | growth factor | inflammation | neurodegeneration

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Section: Discussionsupporting

confidence: 92%

PPARγ-coactivator-1α gene transfer reduces neuronal loss and amyloid-β generation by reducing β-secretase in an Alzheimer’s disease model

Katsouri

Lim

Blondrath

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

123

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“…Therefore, we next examined the role of PPARβ and PPARγ in statin-induced expression of BDNF and NT-3. Although activation of PPARγ has been shown to induce the expression of BDNF (Jin et al, 2013; Kariharan et al, 2015), antisense knockdown of PPARγ and PPARβ failed to inhibit simvastatin-stimulated expression of BDNF and NT-3 in astrocytes (Figure S2D), suggesting that neither PPARβ nor PPARγ is involved in simvastatin-mediated upregulation of neurotrophic factors. However, it is PPARα, but not PPARβ, that is involved in statin-mediated upregulation of neurotrophic factors, as simvastatin stimulated BDNF expression in Pparb null astrocytes (Figure S2E).…”

Section: Resultsmentioning

confidence: 98%

HMG-CoA Reductase Inhibitors Bind to PPARα to Upregulate Neurotrophin Expression in the Brain and Improve Memory in Mice

et al. 2015

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Summary Neurotrophins are important for neuronal health and function. Here, statins, inhibitors of HMG-CoA reductase and cholesterol lowering drugs, were found to stimulate expression of neurotrophins in brain cells independent of the mevalonate pathway. Time-resolved fluorescence resonance energy transfer (FRET) analyses, computer-derived simulation, site-directed mutagenesis, thermal shift assay, and de novo binding followed by electrospray ionization tandem mass spectrometry (ESI-MS) demonstrates that statins serve as ligands of PPARα and that Leu331 and Tyr 334 residues of PPARα are important for statin binding. Upon binding, statins upregulate neurotrophins via PPARα-mediated transcriptional activation of cAMP-response element binding protein (CREB). Accordingly, simvastatin increases CREB and brain-derived neurotrophic factor (BDNF) in the hippocampus of Ppara null mice receiving full-length lentiviral PPARα, but not L331M/Y334D statin-binding domain-mutated lentiviral PPARα. This study identifies statins as ligands of PPARα, describes neurotrophic function of statins via the PPARα-CREB pathway, and analyzes the importance of PPARα in the therapeutic success of simvastatin in an animal model of Alzheimer's disease.

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“…ABA has anti-inflammatory and insulin-sensitizing properties, and there is some evidence suggesting that ABA is a PPARγ agonist [42, 43]. Some reports have shown that PPARγ agonism in the central nervous system ameliorates cognitive function [44, 45]. Therefore, we hypothesized that ABA would alleviate the HFD-induced neuroinflammation and cognitive defects.…”

Section: Discussionmentioning

confidence: 99%

The effect of abscisic acid chronic treatment on neuroinflammatory markers and memory in a rat model of high-fat diet induced neuroinflammation

et al. 2016

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BackgroundWestern diet and lifestyle are associated with overweight, obesity, and type 2 diabetes, which, in turn, are correlated with neuroinflammation processes. Exercise and a healthy diet are important in the prevention of these disorders. However, molecules inhibiting neuroinflammation might also be efficacious in the prevention and/or treatment of neurological disorders of inflammatory etiology. The abscisic acid (ABA) is a phytohormone involved in hydric-stress responses. This compound is not only found in plants but also in other organisms, including mammals. In rodents, ABA can play a beneficial role in the regulation of peripheral immune response and insulin action. Thus, we hypothesized that chronic ABA administration might exert a protective effect in a model of neuroinflammation induced by high-fat diet (HFD).MethodsMale Wistar rats were fed with standard diet or HFD with or without ABA in the drinking water for 12 weeks. Glucose tolerance test and behavioral paradigms were performed to evaluate the peripheral and central effects of treatments. One-Way ANOVA was performed analyzed statistical differences between groups.ResultsThe HFD induced insulin resistance peripherally and increased the levels of proinflammatory markers in in the brain. We observed that ABA restored glucose tolerance in HFD-fed rats, as expected. In addition, chronic ABA treatment rescued cognitive performance in these animals, while not affecting control diet fed animals. Moreover, it counteracted the changes induced by HFD in the hypothalamus; microglia activations and TNFα mRNA levels.ConclusionThese results suggest that ABA might become a new therapeutic molecule improving the neuroinflammatory status and insulin resistance.

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Central activation of PPAR-gamma ameliorates diabetes induced cognitive dysfunction and improves BDNF expression

Cited by 94 publications

References 57 publications

PPARγ-coactivator-1α gene transfer reduces neuronal loss and amyloid-β generation by reducing β-secretase in an Alzheimer’s disease model

PPARγ-coactivator-1α gene transfer reduces neuronal loss and amyloid-β generation by reducing β-secretase in an Alzheimer’s disease model

HMG-CoA Reductase Inhibitors Bind to PPARα to Upregulate Neurotrophin Expression in the Brain and Improve Memory in Mice

The effect of abscisic acid chronic treatment on neuroinflammatory markers and memory in a rat model of high-fat diet induced neuroinflammation

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