Neuronally-directed effects of RXR activation in a mouse model of Alzheimer’s disease

Mariani, Monica; Malm, Tarja; Lamb, Raza; Jay, Taylor R.; Neilson, Lee E.; Casali, Brad T.; Medarametla, L.; Landreth, Gary E.

doi:10.1038/srep42270

Cited by 85 publications

(84 citation statements)

References 62 publications

(122 reference statements)

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“…We chose to examine memory functions of APP/PS1‐mice with the hippocampus‐dependent memory test 1 day after contextual fear conditioning as described before (Kimura & Ohno, ; Mariani et al, ). The mice were 12 months old at the time of experiment to ensure that they have fully developed amyloid pathology (Garcia‐Alloza et al, ; Jackson et al, ; Jankowsky et al, ; Kamphuis et al, ) and memory impairments typically observed in the strain (Kilgore et al, ; Lalonde, Kim, Maxwell, & Fukuchi, ; Minkeviciene et al, ; Volianskis, Kostner, Molgaard, Hass, & Jensen, ).…”

Section: Methodsmentioning

confidence: 99%

PPARβ/δ‐agonist GW0742 ameliorates dysfunction in fatty acid oxidation in PSEN1ΔE9 astrocytes

Konttinen

Gureviciene

Oksanen

et al. 2018

Glia

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Astrocytes are the gatekeepers of neuronal energy supply. In neurodegenerative diseases, bioenergetics demand increases and becomes reliant upon fatty acid oxidation as a source of energy. Defective fatty acid oxidation and mitochondrial dysfunctions correlate with hippocampal neurodegeneration and memory deficits in Alzheimer's disease (AD), but it is unclear whether energy metabolism can be targeted to prevent or treat the disease. Here we show for the first time an impairment in fatty acid oxidation in human astrocytes derived from induced pluripotent stem cells of AD patients. The impairment was corrected by treatment with a synthetic peroxisome proliferator activated receptor delta (PPARβ/δ) agonist GW0742 which acts to regulate an array of genes governing cellular metabolism. GW0742 enhanced the expression of CPT1a, the gene encoding for a rate‐limiting enzyme of fatty acid oxidation. Similarly, treatment of a mouse model of AD, the APP/PS1‐mice, with GW0742 increased the expression of Cpt1a and concomitantly reversed memory deficits in a fear conditioning test. Although the GW0742‐treated mice did not show altered astrocytic glial fibrillary acidic protein‐immunoreactivity or reduction in amyloid beta (Aβ) load, GW0742 treatment increased hippocampal neurogenesis and enhanced neuronal differentiation of neuronal progenitor cells. Furthermore, GW0742 prevented Aβ‐induced impairment of long‐term potentiation in hippocampal slices. Collectively, these data suggest that PPARβ/δ‐agonism alleviates AD related deficits through increasing fatty acid oxidation in astrocytes and improves cognition in a transgenic mouse model of AD.

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Section: Methodsmentioning

confidence: 99%

PPARβ/δ‐agonist GW0742 ameliorates dysfunction in fatty acid oxidation in PSEN1ΔE9 astrocytes

Konttinen

Gureviciene

Oksanen

et al. 2018

Glia

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“…The two times higher PPAR-α expression in males versus females could be responsible for the improvement of synaptic plasticity in male cognition-impaired mice by pemafibrate. PPARs and RXR receptors activation upregulates the expression of several synaptic related genes coding proteins engaged in excitatory neurotransmission [12,36]. Probably through these mechanism agonists of PPAR-α may have a promising effect in a mouse model of aging-dependent cognitive impairments [37,38].…”

Section: Ppar-α and Its Role In Neurotransmission In The Brainmentioning

confidence: 99%

The Novel Role of PPAR Alpha in the Brain: Promising Target in Therapy of Alzheimer’s Disease and Other Neurodegenerative Disorders

et al. 2020

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Peroxisome proliferator activated receptor alpha (PPAR-α) belongs to the family of ligand-regulated nuclear receptors (PPARs). These receptors after heterodimerization with retinoid X receptor (RXR) bind in promotor of target genes to PPAR response elements (PPREs) and act as a potent transcription factors. PPAR-α and other receptors from this family, such as PPAR-β/δ and PPAR-γ are expressed in the brain and other organs and play a significant role in oxidative stress, energy homeostasis, mitochondrial fatty acids metabolism and inflammation. PPAR-α takes part in regulation of genes coding proteins that are involved in glutamate homeostasis and cholinergic/dopaminergic signaling in the brain. Moreover, PPAR-α regulates expression of genes coding enzymes engaged in amyloid precursor protein (APP) metabolism. It activates gene coding of α secretase, which is responsible for non-amyloidogenic pathway of APP degradation. It also down regulates β secretase (BACE-1), the main enzyme responsible for amyloid beta (Aβ) peptide release in Alzheimer Diseases (AD). In AD brain expression of genes of PPAR-α and PPAR-γ coactivator-1 alpha (PGC-1α) is significantly decreased. PPARs are altered not only in AD but in other neurodegenerative/neurodevelopmental and psychiatric disorder. PPAR-α downregulation may decrease anti-oxidative and anti-inflammatory processes and could be responsible for the alteration of fatty acid transport, lipid metabolism and disturbances of mitochondria function in the brain of AD patients. Specific activators of PPAR-α may be important for improvement of brain cells metabolism and cognitive function in neurodegenerative and neurodevelopmental disorders.

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“…Changes in ETV1 expression have likewise been linked with cognitive decline (Abe et al, 2011;Ding et al, 2016). RXR agonists that increase binding to the RXR motif have been shown to enhance synaptic density and improve cognitive function in mouse models of aging and Alzheimer's disease (Cramer et al, 2012;Nam et al, 2016;Tachibana et al, 2016;Mariani et al, 2017). The binding partner of GABPA, METTL23, has been reported to play an essential role in human cognition (Reiff et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Age-Associated DNA Methylation Patterns Are Shared Between the Hippocampus and Peripheral Blood Cells

et al. 2020

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As the population ages, interest in identifying biomarkers of healthy aging and developing antiaging interventions has increased. DNA methylation has emerged as a potentially powerful molecular marker of aging. Methylation changes at specific sites in the human genome that have been identified in peripheral blood have been used as robust estimators of chronological age. Similar age-related DNA methylation signatures are also seen in various tissue types in rodents. However, whether these peripheral alterations in methylation status reflect changes that also occur in the central nervous system remains unknown. This study begins to address this issue by identifying age-related methylation patterns in the hippocampus and blood of young and old mice. Reducedrepresentation bisulfite sequencing (RBSS) was used to identify differentially methylated regions (DMRs) in the blood and hippocampus of 2-and 20-month-old C57/Bl6 mice. Of the thousands of DMRs identified genome-wide only five were both found in gene promoters and significantly changed in the same direction with age in both tissues. We analyzed the hippocampal expression of these five hypermethylated genes and found that three were expressed at significantly lower levels in aged mice [suppressor of fused homolog (Sufu), nitric oxide synthase 1 (Nos1) and tripartite motif containing 2 (Trim2)]. We also identified several transcription factor binding motifs common to both hippocampus and blood that were enriched in the DMRs. Overall, our findings suggest that some agerelated methylation changes that occur in the brain are also evident in the blood and could have significant translational relevance.

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Neuronally-directed effects of RXR activation in a mouse model of Alzheimer’s disease

Cited by 85 publications

References 62 publications

PPARβ/δ‐agonist GW0742 ameliorates dysfunction in fatty acid oxidation in PSEN1ΔE9 astrocytes

PPARβ/δ‐agonist GW0742 ameliorates dysfunction in fatty acid oxidation in PSEN1ΔE9 astrocytes

The Novel Role of PPAR Alpha in the Brain: Promising Target in Therapy of Alzheimer’s Disease and Other Neurodegenerative Disorders

Age-Associated DNA Methylation Patterns Are Shared Between the Hippocampus and Peripheral Blood Cells

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