Activation of PPARα enhances astroglial uptake and degradation of β-amyloid

Raha, Sumita; Ghosh, Arunava; Dutta, Debashis; Patel, Dhruv; Pahan, Kalipada

doi:10.1126/scisignal.abg4747

Cited by 41 publications

(35 citation statements)

References 61 publications

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“…Next day corresponding secondary antibody tagged with specific fluorophore (1:10,000; Jackson Immuno-Research) and the blots were scanned under Odyssey infrared scanner (Li-COR, Lincoln, NE). Band intensities were quantified using ImageJ software (NIH, USA) [ 38 – 40 ].…”

Section: Methodsmentioning

confidence: 99%

Protection of dopaminergic neurons in hemiparkinsonian monkeys by flavouring ingredient glyceryl tribenzoate

Rangasamy

Dutta

Mondal

et al. 2022

NeuroImmune Pharmacology and Therapeutics

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Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease and this study underlines the significance of a small molecule glyceryl tribenzoate (GTB), a FDA approved food additive, in preventing parkinsonian pathologies in MPTP-induced animal models. The study conducted in MPTP-induced mice demonstrated dose-dependent protection of nigral tyrosine hydroxylase (TH) and striatal dopamine level by GTB oral treatment and the optimum dose was found to be 50 mg/kg/d. In the next phase, the study was carried out in MPTP-injected hemiparkinsonian monkeys, which recapitulate better clinical parkinsonian syndromes. GTB inhibited MPTP-driven induction of glial inflammation, which was evidenced by reduced level of GTP-p21Ras and phospho-p65 in SN of monkeys. It led to decreased expression of inflammatory markers such as IL-1β and iNOS. Simultaneously, GTB oral treatment protected nigral TH cells, striatal dopamine, and improved motor behaviour of hemiparkinsonian monkeys. Presence of sodium benzoate, a GTB metabolite and a FDA-approved drug for urea cycle disorders and glycine encephalopathy, in the brain suggests that the neuroprotective effect imparted by GTB might be mediated by sodium benzoate. Although the mechanism of action of GTB is poorly understood, the study sheds light on the therapeutic possibility of a food additive GTB in PD.

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Section: Methodsmentioning

confidence: 99%

Protection of dopaminergic neurons in hemiparkinsonian monkeys by flavouring ingredient glyceryl tribenzoate

Rangasamy

Dutta

Mondal

et al. 2022

NeuroImmune Pharmacology and Therapeutics

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“…In AD, PPARα is involved in the regulation of beta-secretase (BACE-1), an enzyme responsible for the cleavage and later formation of Aβ plaques, and studies have shown a significant downregulation of PPARα in AD pathology ( Wójtowicz et al, 2020 ). Furthermore, treatment with the PPARα agonist gemfibrozil together with retinoic acid (GFB-RA) was recently shown to lower amyloid plaque burden, improve memory, and reduce astrogliosis in mice ( Chandra and Pahan, 2019 ; Raha et al, 2021 ). These effects appear to be mediated by astrocytes through lysosomal biogenesis and autophagy pathways ( Raha et al, 2021 ), although alternative mechanisms of PPAR-regulated activity, such as molecular transrepression, may also be involved ( Ricote and Glass, 2007 ; Pawlak et al, 2014 ).…”

Section: Treatment Strategies Targeting Diet and Lipid-signaling Casc...mentioning

confidence: 99%

“…Furthermore, treatment with the PPARα agonist gemfibrozil together with retinoic acid (GFB-RA) was recently shown to lower amyloid plaque burden, improve memory, and reduce astrogliosis in mice ( Chandra and Pahan, 2019 ; Raha et al, 2021 ). These effects appear to be mediated by astrocytes through lysosomal biogenesis and autophagy pathways ( Raha et al, 2021 ), although alternative mechanisms of PPAR-regulated activity, such as molecular transrepression, may also be involved ( Ricote and Glass, 2007 ; Pawlak et al, 2014 ). GFB-RA has also been shown to stimulate two succeeding neuroprotective pathways that result in the degradation of beta-amyloid plaques.…”

Section: Treatment Strategies Targeting Diet and Lipid-signaling Casc...mentioning

confidence: 99%

“…GFB-RA has also been shown to stimulate two succeeding neuroprotective pathways that result in the degradation of beta-amyloid plaques. These pathways include (1) activation of the transcription factor EB (TFEB) and (2) activation of the low-density lipoprotein receptor (LDLR; Raha et al, 2021 ). LDLR knockout mice treated with GFB-RA were shown to have significantly decreased levels of astrocytic Aβ plaque uptake, suggesting an important role for LDLR in the transport of Aβ ( Raha et al, 2021 ).…”

Section: Treatment Strategies Targeting Diet and Lipid-signaling Casc...mentioning

confidence: 99%

“…These pathways include (1) activation of the transcription factor EB (TFEB) and (2) activation of the low-density lipoprotein receptor (LDLR; Raha et al, 2021 ). LDLR knockout mice treated with GFB-RA were shown to have significantly decreased levels of astrocytic Aβ plaque uptake, suggesting an important role for LDLR in the transport of Aβ ( Raha et al, 2021 ). In the 5XFAD mouse model of AD, GFB-RA treatment was also shown to improve autophagic flux by restoring normal levels of p62 ( Raha et al, 2021 ), a ubiquitin-binding scaffold protein that is degraded by autophagy ( Bjørkøy et al, 2009 ).…”

Section: Treatment Strategies Targeting Diet and Lipid-signaling Casc...mentioning

confidence: 99%

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A Dichotomous Role for FABP7 in Sleep and Alzheimer’s Disease Pathogenesis: A Hypothesis

et al. 2022

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Fatty acid binding proteins (FABPs) are a family of intracellular lipid chaperone proteins known to play critical roles in the regulation of fatty acid uptake and transport as well as gene expression. Brain-type fatty acid binding protein (FABP7) is enriched in astrocytes and has been implicated in sleep/wake regulation and neurodegenerative diseases; however, the precise mechanisms underlying the role of FABP7 in these biological processes remain unclear. FABP7 binds to both arachidonic acid (AA) and docosahexaenoic acid (DHA), resulting in discrete physiological responses. Here, we propose a dichotomous role for FABP7 in which ligand type determines the subcellular translocation of fatty acids, either promoting wakefulness aligned with Alzheimer’s pathogenesis or promoting sleep with concomitant activation of anti-inflammatory pathways and neuroprotection. We hypothesize that FABP7-mediated translocation of AA to the endoplasmic reticulum of astrocytes increases astrogliosis, impedes glutamatergic uptake, and enhances wakefulness and inflammatory pathways via COX-2 dependent generation of pro-inflammatory prostaglandins. Conversely, we propose that FABP7-mediated translocation of DHA to the nucleus stabilizes astrocyte-neuron lactate shuttle dynamics, preserves glutamatergic uptake, and promotes sleep by activating anti-inflammatory pathways through the peroxisome proliferator-activated receptor-γ transcriptional cascade. Importantly, this model generates several testable hypotheses applicable to other neurodegenerative diseases, including amyotrophic lateral sclerosis and Parkinson’s disease.

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Astrocyte–Neuron Interactions in Alzheimer’s Disease

Muñoz-Castro,

Serrano-Pozo

2024

Advances in Neurobiology

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Activation of PPARα enhances astroglial uptake and degradation of β-amyloid

Abstract: A drug combination turns neuroinflammatory astrocytes into neuroprotective, amyloid-clearing cells.

Cited by 41 publications

References 61 publications

Protection of dopaminergic neurons in hemiparkinsonian monkeys by flavouring ingredient glyceryl tribenzoate

Protection of dopaminergic neurons in hemiparkinsonian monkeys by flavouring ingredient glyceryl tribenzoate

A Dichotomous Role for FABP7 in Sleep and Alzheimer’s Disease Pathogenesis: A Hypothesis

Astrocyte–Neuron Interactions in Alzheimer’s Disease

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