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Astrocyte-neuron lactate shuttle plays a pivotal role in sensory-based neuroprotection in a rat model of permanent middle cerebral artery occlusion.

ABSTRACT: We have previously demonstrated protection from impending cortical ischemic stroke is achievable by sensory stimulation of the ischemic area in an adult rat model of permanent middle cerebral artery occlusion (pMCAo). We have further demonstrated that a major underpinning mechanism that is necessary for such protection is the system of collaterals among cerebral arteries that results in reperfusion of the MCA ischemic territory. However, since such collateral flow is weak, it may be necessary but not sufficient for protection and therefore we sought other complementary mechanisms that contribute to sensory-based protection. We hypothesized that astrocytes-neuron lactate shuttle (ANLS) activation could be another potential underpinning mechanism that complements collateral flow in the protection process. Supporting our hypothesis, using functional imaging, pharmacological treatments, and postmortem histology, we showed that ANLS played a pivotal role in sensory stimulation-based protection of cortex and therefore serves as the other supporting mechanism underpinning the protection process.

SUBMITTER: Bhatti MS

PROVIDER: S-EPMC10406860 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Astrocyte-neuron lactate shuttle plays a pivotal role in sensory-based neuroprotection in a rat model of permanent middle cerebral artery occlusion.

Bhatti Mehwish S MS Frostig Ron D RD

Scientific reports 20230807 1

We have previously demonstrated protection from impending cortical ischemic stroke is achievable by sensory stimulation of the ischemic area in an adult rat model of permanent middle cerebral artery occlusion (pMCAo). We have further demonstrated that a major underpinning mechanism that is necessary for such protection is the system of collaterals among cerebral arteries that results in reperfusion of the MCA ischemic territory. However, since such collateral flow is weak, it may be necessary bu ...[more]

PMID: 37550353

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Project description:A viewpoint considering Alzheimer's disease (AD) as "type 3 diabetes" emphasizes the pivotal role of dysfunctional brain energy metabolism in AD. The hormone fibroblast growth factor 21 (FGF21) is a crucial regulator in energy metabolism; however, our understanding of the therapeutic potential and mechanisms underlying the effect of FGF21 on neurodegeneration of AD is far from complete. Methods: To further elucidate the effect of FGF21 on AD-related neurodegeneration, we used APP/PS1 transgenic mice to assess the effects of FGF21 on memory dysfunction, amyloid plaque pathology and pathological tau hyperphosphorylation. We also established an in vitro system to mimic astrocyte-neuron communication and an in vivo model of acute injury. Based on the in vivo and in vitro models, we analyzed the neuroprotective actions of FGF21 and pathways related to astrocyte-neuron communication and further focused on the astrocyte-neuron lactate shuttle system. Results: Here, we report that FGF21 can ameliorate Alzheimer-like neurodegeneration in APP/PS1 transgenic mice. We detected defects in the astrocyte-neuron lactate shuttle system in the in vivo and in vitro models of AD and identified FGF21 as a neuroprotective molecule that can rescue these deficits. Administration of FGF21 can alleviate memory dysfunction, amyloid plaque pathology and pathological tau hyperphosphorylation, and the function of FGF21 in neurodegeneration is mediated in part by monocarboxylate transporters (MCTs). In vivo evidence also suggests that FGF21 acts centrally in mice to exert its effects on neurodegeneration and energy metabolism via its regulation of MCTs. Conclusions: These results suggest that FGF21 alters metabolic parameters to mediate its neuroprotective functions. Modulation of the astrocyte-neuron lactate shuttle system can be one of the most efficient strategies for FGF21 in Alzheimer-like degeneration and contributes to improvements in brain metabolic defects and amyloid β-induced cytotoxicity. Our findings provide insights into the mechanisms underlying the effects of FGF21 on neurodegeneration and brain energy metabolism and suggest that FGF21 may have therapeutic value in the treatment of AD and other neurodegenerative diseases.

Dataset Information

Astrocyte-neuron lactate shuttle plays a pivotal role in sensory-based neuroprotection in a rat model of permanent middle cerebral artery occlusion.

Publications

Astrocyte-neuron lactate shuttle plays a pivotal role in sensory-based neuroprotection in a rat model of permanent middle cerebral artery occlusion.

Similar Datasets

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