Lactate Signaling Mediated by AMD3100 Ameliorates Astrocyte Pathology and Remyelination Without Additional Extension of SOD1G93A Mice' Life-Span

Rabinovich-Nikitin, I.; Solomon, B.

doi:10.1101/2022.01.28.478264

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bioRxiv · 10.1101/2022.01.28.478264

Lactate Signaling Mediated by AMD3100 Ameliorates Astrocyte Pathology and Remyelination Without Additional Extension of SOD1G93A Mice' Life-Span

Rabinovich-Nikitin, I.·Solomon, B.

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Abstract

BackgroundAmyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of motor neurons accompanied by the accumulation of the morphologically and functionally altered glial cells. Reactive astrocytes and microglia secrete pro-inflammatory mediators and contribute to disease progression. Notably, oligodendrocyte functions are disrupted in ALS, including trophic support, myelination, and oligodendrocyte differentiation. ALS patients and mutant SOD1 mice models display reduced levels of myelin basic protein (MBP) and monocarboxylate transporter 1 (MCT1) contributing to impairment of oligodendrocyte function. Lactate, an active metabolite capable of moving into or out of cells, acts as a signaling molecule, transported exclusively by monocarboxylate transporters (MCTs). We showed previously, that AMD3100 increases the lactate transporter MCT1 in an animal models of Alzheimers disease (AD) and ALS. Methods and ResultsAMD3100 is a reversible antagonist of CXCR4, and therefore inhibits the CXCR4/CXCL12 axis. AMD3100 was shown to have beneficial effects on extension of SOD1G93A mice life-span and enabling migration of hematopoietic stem cells (HSPCs) from bone marrow to periphery. The low content of lactate and transporters in SOD1G93A mice model led us to propose a combined treatment with AMD3100 and exogeneous L-lactate. ConclusionsThe combined treatment attenuated neuroinflammation and remyelination but did not have a significant extension of SOD1G93A mice life-span compared with AMD3100 treatment alone.

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Rabinovich-Nikitin, I., Solomon, B.. 2022-01-29. Lactate Signaling Mediated by AMD3100 Ameliorates Astrocyte Pathology and Remyelination Without Additional Extension of SOD1G93A Mice' Life-Span. https://doi.org/10.1101/2022.01.28.478264

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