TRPV1 sustains microglial metabolic reprogramming in Alzheimer's disease

Lu, Jia; Wei, Zhou; Dou, Fangfang; Wang, Chenfei; Yu, Zhihua

doi:10.15252/embr.202052013

Cited by 67 publications

(76 citation statements)

References 74 publications

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“…Metabolic reprogramming is a common phenomenon observed in several diseases, including cancer and viral infections ( Sanchez and Lagunoff, 2015 ; Medina, 2020 ; Polcicova et al, 2020 ). Metabolic reprogramming is also observed in many neurodegenerative diseases like Alzheimer’s disease, Amyotrophic Lateral Sclerosis (ALS), and Parkinson’s disease ( Han et al, 2021 ; Lu et al, 2021 ). However, little is known about metabolic reprogramming in neurons affected by HIV-1 and the role metabolic reprogramming plays in the progression of HAND.…”

Section: Discussionmentioning

confidence: 99%

Metabolic Reprogramming in HIV-Associated Neurocognitive Disorders

Allen

Arjona

Santerre

et al. 2022

Front. Cell. Neurosci.

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A significant number of patients infected with HIV-1 suffer from HIV-associated neurocognitive disorders (HAND) such as spatial memory impairments and learning disabilities (SMI-LD). SMI-LD is also observed in patients using combination antiretroviral therapy (cART). Our lab has demonstrated that the HIV-1 protein, gp120, promotes SMI-LD by altering mitochondrial functions and energy production. We have investigated cellular processes upstream of the mitochondrial functions and discovered that gp120 causes metabolic reprogramming. Effectively, the addition of gp120 protein to neuronal cells disrupted the glycolysis pathway at the pyruvate level. Looking for the players involved, we found that gp120 promotes increased expression of polypyrimidine tract binding protein 1 (PTBP1), causing the splicing of pyruvate kinase M (PKM) into PKM1 and PKM2. We have also shown that these events lead to the accumulation of advanced glycation end products (AGEs) and prevent the cleavage of pro-brain-derived neurotrophic factor (pro-BDNF) protein into mature brain-derived neurotrophic factor (BDNF). The accumulation of proBDNF results in signaling that increases the expression of the inducible cAMP early repressor (ICER) protein which then occupies the cAMP response element (CRE)-binding sites within the BDNF promoters II and IV, thus altering normal synaptic plasticity. We reversed these events by adding Tepp-46, which stabilizes the tetrameric form of PKM2. Therefore, we concluded that gp120 reprograms cellular metabolism, causing changes linked to disrupted memory in HIV-infected patients and that preventing the disruption of the metabolism presents a potential cure against HAND progression.

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Section: Discussionmentioning

confidence: 99%

Metabolic Reprogramming in HIV-Associated Neurocognitive Disorders

Allen

Arjona

Santerre

et al. 2022

Front. Cell. Neurosci.

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“…Cell metabolism was measured by a Seahorse XFe cell analyzer (Agilent Technologies, Inc., Santa Clara, CA, United States) as previously described ( Lu et al, 2021 ). Shortly, BV2 cells were plated in the XF96 cell culture microplates at 1 × 10 5 cells/well, and after adherence overnight.…”

Section: Methodsmentioning

confidence: 99%

“…The autophagy levels were measured as previously reported ( Lu et al, 2021 ). In brief, the BV2 cells and primary microglia were seeded at a density of 1 × 10 5 cells/well and cultured overnight, after which cells were transfected with mRFP-GFP-LC3 plasmids (Addgene, Inc., Watertown, MA, United States) for 48 h according to the manufacturer’s protocol (Guangzhou RiboBio Co., Ltd, Guangzhou, China).…”

Section: Methodsmentioning

confidence: 99%

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TRPV1-Mediated Microglial Autophagy Attenuates Alzheimer’s Disease-Associated Pathology and Cognitive Decline

Wang

Huang

et al. 2022

Front. Pharmacol.

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Autophagy is a major regulator of the ageing process of the central nervous system and neurodegeneration. Autophagy dysfunction has been implicated in the pathogenesis of Alzheimer’s disease (AD). TRPV1 was reported to regulate autophagy to protect against foam cell formation and reduce the release of inflammatory factors in atherosclerosis. In this study, pharmacological activation of TRPV1 with the TRPV1 agonist capsaicin induced autophagy in a TRPV1-dependent manner in both primary microglia and BV2 cells. TRPV1-mediated autophagy regulated glycolysis and oxidative phosphorylation by controlling the expression of genes required for aerobic glycolysis and mitochondrial respiration in primary microglia. TRPV1 agonist capsaicin decreased amyloid and phosphorylated tau pathology and reversed memory deficits by promoting microglia activation, metabolism, and autophagy in 3xTg mice. These results indicate that TRPV1 was a potential therapeutic target for AD, which suggests that capsaicin should be further assessed as a possible treatment for AD.

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“…Notably, impaired autophagic flux was correlated with ageing, characterized by immune senescence of macrophages [ 158 ]. In APP/PS1 mice, TRPV1 activation downregulated the release of pro-inflammatory IL-6, TNF-α, and increased autophagy, which promoted the clearance of Aβ [ 127 ].…”

Section: Microglial Endocannabinoid System In Alzheimer’s Diseasementioning

confidence: 99%

Microglial Endocannabinoid Signalling in AD

Scipioni

Ciaramellano

Carnicelli

et al. 2022

Cells

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Chronic inflammation in Alzheimer’s disease (AD) has been recently identified as a major contributor to disease pathogenesis. Once activated, microglial cells, which are brain-resident immune cells, exert several key actions, including phagocytosis, chemotaxis, and the release of pro- or anti-inflammatory mediators, which could have opposite effects on brain homeostasis, depending on the stage of disease and the particular phenotype of microglial cells. The endocannabinoids (eCBs) are pleiotropic bioactive lipids increasingly recognized for their essential roles in regulating microglial activity both under normal and AD-driven pathological conditions. Here, we review the current literature regarding the involvement of this signalling system in modulating microglial phenotypes and activity in the context of homeostasis and AD-related neurodegeneration.

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TRPV1 sustains microglial metabolic reprogramming in Alzheimer's disease

Cited by 67 publications

References 74 publications

Metabolic Reprogramming in HIV-Associated Neurocognitive Disorders

Metabolic Reprogramming in HIV-Associated Neurocognitive Disorders

TRPV1-Mediated Microglial Autophagy Attenuates Alzheimer’s Disease-Associated Pathology and Cognitive Decline

Microglial Endocannabinoid Signalling in AD

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