期刊
ALZHEIMERS RESEARCH & THERAPY
卷 13, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s13195-020-00766-4
关键词
Tauopathy; Alzheimer's disease; Mouse model; Erythropoietin; Neuroinflammation; Microglia
资金
- VA office of research and development [I01 RX001305-01A2]
- National Institutes of Health [X01 NS073526-01A1]
- New Jersey Commission on Brain Injury Research [CBIR20IRG007]
- Segal Fund
Treatment of PS19 mice with JM4 before disease onset reduced neurological deficits, prolonged lifespan, and rescued memory impairment. The beneficial effects were accompanied by reductions in neuronal loss, phosphorylated tau aggregation, and microglial activation in the PS19 mouse brain, suggesting JM4 as a potential novel therapeutic agent for tauopathies including AD and related dementias.
Background: Prominent activation of microglial immune/inflammatory processes is a characteristic feature of brains of patients with tauopathies including Alzheimer's disease (AD), suggesting that neuroinflammation may be a critical factor in their pathogenesis. Strategies aimed at developing new therapeutics for tauopathies based on anti-inflammation or immunomodulation are likely to be promising avenues of research. We previously developed JM4-a 19'mer cyclic peptide derived from the first loop of human erythropoietin. This peptide possesses beneficial immune modulatory and tissue protective effects while lacking the undesirable side effects of full-length erythropoietin. In this preclinical study, we investigated the effect of chronic JM4 treatment on the PS19 mouse that carries the P301S mutant human tau gene, linked to a form of frontotemporal dementia. This transgenic mouse has been widely used as a model of tauopathies including AD and related dementias. Methods: Daily subcutaneous treatment of female PS19 mice with JM4 was initiated before disease onset and continued on for the animals' lifespan. The progression of neurological deficit and the lifespan of these mice were assessed. To evaluate the effect of JM4 treatment on cognition of these animals, the PS19 mice underwent Barnes maze test and elevated plus maze test. In addition, neuronal loss, phosphorylated tau aggregation, and microglial activation were assessed using immunohistochemistry of PS19 mouse brain sections. Results: JM4 treatment of PS19 mice initiated before disease onset reduced neurological deficit, prolonged lifespan, and rescued memory impairment. The beneficial effects of JM4 were accompanied by reductions in neuronal loss, phosphorylated tau aggregation, and microglial activation in the PS19 mouse brain. Limitations: Use of a single dose of JM4 and female mice only. Conclusion: JM4 is a potential novel therapeutic agent for the treatment of tauopathies including AD and related dementias.
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