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

Abstract

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.

Tumor necrosis factor alpha mediates orofacial discomfort in an occlusal dental interference model in rats: The role of trigeminal ganglion inflammation

“…In our study, the infliximab group showed a high immunostaining of PPARγ and low immunostaining of TNF‐α. Exposure to M2 (anti‐inflammatory microglia) supernatant induced PPARγ expression and activated neural stem/progenitor cells, increasing and reducing neural inflammation and GFAP + astrocyte cells . And similar to our study, in each the GFAP was increased in saline group, in experimental models of temporomandibular joint inflammation‐induced hypernociception, GFAP overexpression was directly associated with morphological alterations of the trigeminal nerve …”

“…The PPAR‐γ agonist pioglitazone effectively reduced symptoms of depression induced by sciatic nerve ligation causing neuropathic pain in chronic constriction injury, and PPAR‐γ activators have been documented to attenuate spinal nerve transection and partial sciatic nerve ligation‐induced neuropathic pain . Moreover, PPARβ/δ/β agonists ameliorate dysfunction in fatty acid oxidation and glial fibrillary acidic protein (GFAP)‐immunoreactivity in PSEN1Δ/ΒE9 astrocytes, suggesting that transient nNOS trigeminal overexpression (spiked after one day of ODI induction) can be suppressed by PPAR.…”

Modeling Alzheimer’s disease with iPSC-derived brain cells

“…Astrocytes generated from patients carrying both FAD-linked PSEN1 M146L and SAD-linked APOE4 mutations exhibited reduced morphological complexity and altered localization of marker proteins, indicating similar effects of FAD and SAD mutations [126]. PSEN1 ΔE9 astrocytes showed elevated release and reduced uptake of Aβ 42 , altered Ca 2+ homeostasis, increased reactive oxygen species production, altered cytokine release and impaired fatty acid oxidation [128,129]. iPSC-derived astrocytes have also been shown to promote the survival, maturation and function of cocultured human neurons, effects that can be impaired by PSEN1 ΔE9 and APOE4 mutations [128,130,131].…”

Mitochondrial Metabolism in Astrocytes Regulates Brain Bioenergetics, Neurotransmission and Redox Balance

“…Other FAO modulators include the CPT1a inhibitor oxfenicine and PPARs agonists/antagonists. Accordingly, the impairment in FAO observed in astrocytes derived from induced pluripotent stem cells isolated from Alzheimer's disease patients is corrected by PPARβ/δ agonists (Konttinen et al, 2019). The specificity of the metabolic modifiers ranolazine (Ranexa) and trimetazidine, initially described as partial FAO inhibitors that target the HAD (or 3-KAT) activity of the trifunctional protein HADHA, has been recently questioned (Ma et al, 2020).…”