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

Abstract

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.

The Effects of a Blood–Brain Barrier Penetrating Erythropoietin in a Mouse Model of Tauopathy

“…Chronic treatment with the cTfRMAb-EPO fusion protein markedly reduced the AT8-positive pTau immunoreactive area in the PS19 mice compared to the saline-treated PS19 mice in all of the analyzed brain regions (Figure 2). This is consistent with a recent study that shows that an EPO-derived peptide can reduce AT8positive pTau in 10-month-old PS19 mice [19]. Although the BBB-penetrating EPO did not completely reduce the AT8-positive area to the WT levels in our hands, the AT8-positive area was reduced by 50% or more compared to the saline-treated PS19 mice (Figure 2).…”

“…Although there is a growing body of literature reporting the protective effects of EPO on amyloid pathology [18], studies reporting the effect of EPO on Aβ-independent tau pathology are limited. In this respect, the use of a low molecular weight EPO-derived peptide that penetrates the BBB was reported to mitigate neurological deficits and neuropathological changes in female PS19 mice [19]. The PS19 mice express the P301S mutant human tau, resulting in hyperphosphorylated tau and NFT-like inclusions with age [20], microgliosis and astrocytosis [21], and age-dependent brain atrophy and neuronal loss in the hippocampus, neocortex, and entorhinal cortex [21] in the absence of Aβ pathology.…”

A prolyl oligopeptidase inhibitor reduces tau pathology in cellular models and in mice with tauopathy

“…There have been various attempts to alleviate or prevent the progression of tau-related pathology in the PS19 transgenic mouse model of tauopathy. These include immunomodulatory treatments ( 63 – 66 ), enhanced clearance of senescent glial cells ( 67 ), immunization against pathological tau ( 68 ), microtubule stabilizers ( 69 – 71 ), aggregation inhibitors ( 72 , 73 ), and metabolic modulators ( 74 ). However, in most of these studies, the treatment was started well before symptom onset, with limited relevance to the clinical situation.…”

Does Inflammation Play a Major Role in the Pathogenesis of Alzheimer's Disease?

“…Treatment of PS19 mice with JM4, which is a 19-mer cyclic peptide derived from the first loop of human erythropoietin with immunomodulatory properties, before the onset of AD reduced the neurological deficit and reduced memory impairment. The prior anti-inflammatory therapy may reduce the progression of Alzheimer's disease in the early stages of AD (Choi et al, 2021). Also, in studies in murine AD models, nilvadipine, used in the treatment of arterial hypertension, effectively reduces inflammation, tau protein hyperphosphorylation, and improves memory (Morin et al, 2020).…”