Erythropoietin-derived peptide treatment reduced neurological deficit and neuropathological changes in a mouse model of tauopathy.

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.

Caspase-1 expression in multiple sclerosis plaques and cultured glial cells.

Caspase-1 is responsible for processing inflammatory cytokines and is associated with the induction of apoptosis. Using RT-PCR, we found that caspase-1 mRNA transcripts from frozen brain extracts were significantly elevated in multiple sclerosis (MS) compared to controls. Immunohistochemical staining using a specific antiserum confirmed the marked up regulation of caspase-1 within acute and chronic MS plaques, while little staining was seen in control brains. In addition to the expected caspase-1 expression in microglia and infiltrating perivascular mononuclear cells, we found that cytoplasmic caspase-1 expression was sharply increased in the resident oligodendrocytes of MS lesions. The TUNEL reaction for fragmented DNA co-localized over an occasional caspase-1-expressing cell and large numbers of caspase-1-positive "corpses" were observed within phagocytic macrophages of an acute evolving MS lesion. Studies using an immortalized human oligodendroglial hybrid cell line exposed to cytokine challenge showed that death induction was blocked by the caspase-1-like inhibitor Z-YVAD-fmk, while the caspase-3-like inhibitor Z-DEVD-fmk was less effective. Cellular levels of procaspase-1 were reduced compared to controls in oligodendroglia induced to die by cytokine challenge, as judged by Western immunoblotting. Our results suggest that caspase-1 may play a role in the inflammatory and apoptotic processes associated with MS pathogenesis.