PGC-1α Expression Decreases in the Alzheimer Disease Brain as a Function of Dementia

Qin, Weiping; Haroutunian, Vahram; Katsel, Pavel; Cardozo, Christopher P.; Ho, Lap; Buxbaum, Joseph D.; Pasinetti, Giulio Maria

doi:10.1001/archneurol.2008.588

Cited by 325 publications

(237 citation statements)

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“…1 Thereby, a decrease in SIRT1 expression has been detected in AD, 40 PD 41 and HD 42 patient brain samples, which is correlated with decreased PGC-1α activity. [43][44][45] Indeed, the promotion of SIRT1 activity either genetically or pharmacologically with RSV, has been shown to combat several pathological hallmarks of neurodegeneration in a variety of models for AD, [46][47][48][49] and HD, 51,52 supporting the neuroprotective notion of SIRT1 activation. However, recent studies have shown diametrically opposed results, indicating that selective SIRT1 inhibitors offer neuroprotection in cells and animal models of HD, 8 or that overexpression of PGC-1α exacerbates β-amyloid and tau deposition in an AD mouse model.…”

Section: Discussionmentioning

confidence: 96%

Activation of sirtuin 1 as therapy for the peroxisomal disease adrenoleukodystrophy

et al. 2015

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Oxidative stress and mitochondrial failure are prominent factors in the axonal degeneration process. In this study, we demonstrate that sirtuin 1 (SIRT1), a key regulator of the mitochondrial function, is impaired in the axonopathy and peroxisomal disease X-linked adrenoleukodystrophy (X-ALD). We have restored SIRT1 activity using a dual strategy of resveratrol treatment or by the moderate transgenic overexpression of SIRT1 in a X-ALD mouse model. Both strategies normalized redox homeostasis, mitochondrial respiration, bioenergetic failure, axonal degeneration and associated locomotor disabilities in the X-ALD mice. These results indicate that the reactivation of SIRT1 may be a valuable strategy to treat X-ALD and other axonopathies in which the control of redox and energetic homeostasis is impaired. Cell Death and Differentiation (2015) 22, 1742-1753 doi:10.1038/cdd.2015; published online 27 March 2015Sirtuins are highly conserved NAD + -dependent deacetylases with a critical impact on metabolic adaptive responses. In mammals, among the seven members of the sirtuin family (SIRT1-SIRT7), SIRT1 has been the most extensively characterized. 1 SIRT1 promotes the generation of new mitochondria through the activation of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), which orchestrates the mitochondrial biogenesis program through the transcriptional activation of nuclear respiratory factors (NRF-1 and NRF-2) and mitochondrial transcription factor A (TFAM). 2 SIRT1 activity is finely regulated not only by gene expression and protein levels but also by posttranslational modifications, its oligomeric status, the interaction with the DBC1 and AROS proteins, and the levels of NAD + /NADH/NAM. 3 In addition, SIRT1 activity is modulated by several synthetic or natural molecules such as the polyphenol resveratrol (3,4',5-trihydroxystilbene: RSV). 4 The activation of SIRT1 by transgenic overexpression or pharmacologically with RSV has been shown to prevent the pathology in diseases commonly associated with mitochondrial dysfunction such as the metabolic syndrome and neurodegenerative disorders, 1,5,6 albeit recent findings cast doubts on the universal validity of the results. 7,8 Although prominent axonal pathology often precedes cell body loss in many neurodegenerative diseases, 9 the potential of SIRT1 activation in axonal degeneration has not been addressed in depth. In this work, we take advantage of the cellular and animal models of the rare monogenic neurodegenerative disease named X-linked adrenoleukodystrophy (X-ALD, (McKusick No.300100)) to evaluate the impact of SIRT1 function on axonal degeneration. X-ALD is the most prevalent peroxisomal disorder (minimum incidence 1:17 000 newborns), characterized by brain inflammatory demyelination and/or axonopathy of long tracts in spinal cords, adrenal insufficiency and a pathognomonic accumulation of very longchain fatty acids (VLCFA) in plasma and tissues, in particular hexacosanoic acid (C26:0). 10,11 The disease phenotypes range from adrenal ...

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Section: Discussionmentioning

confidence: 96%

Activation of sirtuin 1 as therapy for the peroxisomal disease adrenoleukodystrophy

et al. 2015

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“…Neuroprotection through PGC-1 was shown in the contexts of oxidative stress and amyotrophic lateral sclerosis whereas neurodegeneration is associated with a loss of PGC-1 in various disorders including Huntington´s and Alzheimer´s disease [85,[130][131][132]. Consistently, global and brain-specific deletion models of PGC-1 exhibit striatal degenerative lesions and increased susceptibility for other neurodegenerative events [80,133].…”

Section: Other Organ-specific Functions Of Pgc-1 Coactivatorsmentioning

confidence: 96%

Functional crosstalk of PGC-1 coactivators and inflammation in skeletal muscle pathophysiology

Eisele

Handschin

2013

Semin Immunopathol

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(150 -250 words) [165] Skeletal muscle is an organ involved in whole body movement and energy metabolism with the ability to dynamically adapt to different states of (dis-)use. At a molecular level, the peroxisome proliferatoractivated receptor  coactivators 1 (PGC-1) are important mediators of oxidative metabolism in skeletal muscle and in other organs. Musculoskeletal disorders as well as obesity and its sequelae are associated with PGC-1 dysregulation in muscle with a concomitant local or systemic inflammatory reaction. In this review, we outline the function of PGC-1 coactivators in physiological and pathological conditions as well as the complex interplay of metabolic dysregulation and inflammation in obesity with special focus on skeletal muscle. We further put forward the hypothesis that in this tissue, oxidative metabolism and inflammatory processes mutually antagonize each other. The nuclear factor κB (NF-B) pathway thereby plays a key role in linking metabolic and inflammatory programs in muscle cells. We conclude this review with a perspective about the consequences of such a negative crosstalk on the immune system and the possibilities this opens for clinical applications.

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“…PGC-1α has been implicated in various neurodegenerative diseases (6) and its expression is reduced in the brain of AD patients (7,8). Interestingly, exogenous human PGC-1α expression in neuroblastoma cells and in primary neurons from the Tg2576 mouse model of AD decreased Aβ generation and increased nonamyloidogenic sAPPα levels (7,8).…”

mentioning

confidence: 99%

“…Interestingly, exogenous human PGC-1α expression in neuroblastoma cells and in primary neurons from the Tg2576 mouse model of AD decreased Aβ generation and increased nonamyloidogenic sAPPα levels (7,8). Additionally, we showed that PGC-1α mediates this effect by reducing β-APP cleaving enzyme (BACE1) gene transcription via a PPARγ-dependent mechanism (7).…”

mentioning

confidence: 99%

“…Additionally, we showed that PGC-1α mediates this effect by reducing β-APP cleaving enzyme (BACE1) gene transcription via a PPARγ-dependent mechanism (7). Conversely, crossing Tg2576 with mice deficient in PGC-1α or silencing PGC-1α using siRNA transfection in neuronal cells, led to increased Aβ levels (7)(8)(9). Pharmacological stimulation of PGC-1α synthesis with nicotinamide riboside, the precursor of NAD + , resulted in reduced Aβ levels and attenuated cognitive deterioration in Tg2576 mice (9).…”

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confidence: 99%

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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.

110

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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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PGC-1α Expression Decreases in the Alzheimer Disease Brain as a Function of Dementia

Cited by 325 publications

References 58 publications

Activation of sirtuin 1 as therapy for the peroxisomal disease adrenoleukodystrophy

Activation of sirtuin 1 as therapy for the peroxisomal disease adrenoleukodystrophy

Functional crosstalk of PGC-1 coactivators and inflammation in skeletal muscle pathophysiology

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

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