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Chronic JM4 treatment reduced hyperphosphorylated tau aggregates in PS19 mouse brains. a Top row: Images of coronal sections of mouse brains containing the hippocampus at 10 months of age showing AT8 immunoreactivity. Rectangles mark dentate gyrus region and dashed rectangles mark frontal cortex region selected for quantification. × 2 objective. Scale bar 500 μm. Middle row: Magnified images of the hippocampus dentate gyrus region showing AT8 immunoreactivity. × 10 objective. Scale bar 100 μm. Bottom row: Magnified images of the frontal cortex region showing AT8 immunoreactivity. × 10 objective. Scale bar 100 μm. The left panels show abundant strongly positive hyperphosphorylated tau aggregates recognized by the AT8 antibody in PBS sham-treated PS19 mouse brain. The middle panels show dramatically reduced levels of AT8 immunoreactivity in JM4-treated PS19 mouse brain. The right panels show essentially no AT8 immunoreactivity in wild-type mouse brain. b Quantification of AT8 immunoreactivity in the hippocampus dentate gyrus region (*p < 0.05, one-way ANOVA followed by Bonferroni test to compare JM4-treated group and PBS sham-treated group). c Western blots of mouse brain homogenates of PBS sham-treated PS19 mice, JM4-treated PS19 mice, and wild-type (WT) mice showing the immunoreactivity of RAB fraction, RIPA fraction, and urea fraction detected by AT8 antibody. GAPDH served as a loading control. d Quantification of TAU-5 immunoreactivity in the brain slices containing the hippocampus. No statistically significant difference was noted on two-tailed unpaired t test. e Quantitative RT-PCR analysis of human MAPT mRNA levels relative to mouse GAPDH mRNA level in 10 months of age mouse brain lysates. The data was normalized to the mean value of the PBS sham-treated group. No statistically significant difference was noted on two-tailed unpaired t test
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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-inflammatio...
Citations
... This study also showed that when coupled to lipid nanoparticles, the positive benefits of EPO could be increased at lower dosages. 8 Choi et al. [18] Female transgenic PS 19 mouse strain JM4-a 19'mer cyclic peptide derived from the first loop of human erythropoietin, administered subcutaneously. ...
This review aims to explore the potential of Erythropoietin, a glycopeptide hormone, as a treatment option for Alzheimer’s Disease, which is the commonest cause of dementia. Despite years of focus and research, therapeutic options for Alzheimer’s disease are not yet completely satisfactory. And as people age, they are likely to develop Alzheimer’s Disease, further pressuring the healthcare system. So, it is definite to develop treatment options that meet superior outcomes with minimal negative effects. A comprehensive review of the literature was conducted in PubMed and Google Scholar using a combination of keywords, including Alzheimer’s Disease, Dementia, Erythropoietin, and Neuroprotection. Search results were assessed for relevance before using the data for this study. The beneficial implications of erythropoietin as a therapeutic option have been explored, along with the side effects and mechanisms of erythropoietin in Alzheimer’s Disease. Overall, our review indicates that erythropoietin presents a promising avenue for mitigating the progression of Alzheimer’s Disease, with minimal associated side effects.
... 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)(64)(65)(66), enhanced clearance of senescent glial cells (67), immunization against pathological tau (68), microtubule stabilizers (69)(70)(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. ...
Tauopathies are neurodegenerative diseases that are characterized by accumulation of hyperphosphorylated tau protein, higher-order aggregates, and tau filaments. Protein phosphatase 2A (PP2A) is a major tau dephosphorylating phosphatase, and a decrease in its activity has been demonstrated in tauopathies, including Alzheimer's disease. Prolyl oligopeptidase is a serine protease that is associated with neurodegeneration, and its inhibition normalizes PP2A activity without toxicity under pathological conditions. Here, we assessed whether prolyl oligopeptidase inhibition could protect against tau-mediated toxicity in cellular models in vitro and in the PS19 transgenic mouse model of tauopathy carrying the human tau-P301S mutation. We show that inhibition of prolyl oligopeptidase with the inhibitor KYP-2047 reduced tau aggregation in tau-transfected HEK-293 cells and N2A cells as well as in human iPSC-derived neurons carrying either the P301L or tau-A152T mutation. Treatment with KYP-2047 resulted in increased PP2A activity and activation of autophagic flux in HEK-293 cells and N2A cells and in patient-derived iNeurons, as indicated by changes in autophagosome and autophagy receptor markers; this contributed to clearance of insoluble tau. Furthermore, treatment of PS19 transgenic mice for 1 month with KYP-2047 reduced tau burden in the brain and cerebrospinal fluid and slowed cognitive decline according to several behavioral tests. In addition, a reduction in an oxidative stress marker was seen in mouse brains after KYP-2047 treatment. This study suggests that inhibition of prolyl oligopeptidase could help to ameliorate tau-dependent neurodegeneration.
... 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). ...
Alzheimer's disease (AD) is a neurodegenerative disease leading to dementia for which no effective medicine exists. Currently, the goal of therapy is only to slow down the inevitable progression of the disease and reduce some symptoms. AD causes the accumulation of proteins with the pathological structure of Aβ and tau and the induction of inflammation of nerves in the brain, which lead to the death of neurons. The activated microglial cells produce pro-inflammatory cytokines that induce a chronic inflammatory response and mediate synapse damage and the neuronal death. Neuroinflammation has been an often ignored aspect of ongoing AD research. There are more and more scientific papers taking into account the aspect of neuroinflammation in the pathogenesis of AD, although there are no unambiguous results regarding the impact of comorbidities or gender differences. This publication concerns a critical look at the role of inflammation in the progression of AD, based on the results of our own in vitro studies using model cell cultures and other researchers.
... 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. ...
... 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). ...
... These results are consistent with the strong significant positive correlation between the overall AT8-positive area and the overall Iba1-positive area in the 8-month-old PS19 mice [40]. Though we cannot determine if the effects of cTfRMAb-EPO are due to a direct effect on tau phosphorylation and/or microgliosis, these findings suggest significant cross-talk between pTau and microgliosis, and this is consistent with the reduction in phosphorylated tau aggregation and microglial activation observed with the 19'mer EPO-derived cyclic peptide in PS19 mice [19]. ...
Erythropoietin (EPO), a hematopoietic neurotrophin, is a potential therapeutic for Alzheimer’s disease (AD) but has limited blood–brain barrier (BBB) permeability. EPO fused to a chimeric transferrin receptor monoclonal antibody (cTfRMAb) enters the brain via TfR-mediated transcytosis across the BBB. We previously showed that cTfRMAb-EPO is protective in a mouse model of amyloidosis, but its effects on tauopathy are not known. Given that amyloid and tau pathology are characteristics of AD, the effects of cTfRMAb-EPO were studied in a tauopathy mouse model (PS19). Six-month-old PS19 mice were injected intraperitoneally with either saline (PS19-Saline; n = 9) or cTfRMAb-EPO (PS19-cTfRMAb-EPO, 10 mg/kg; n = 10); every two or three days on alternate weeks for 8 weeks. Age-matched, saline-treated, wildtype littermates (WT-Saline; n = 12) were injected using the same protocol. After 8 weeks, locomotion, hyperactivity, and anxiety were assessed via the open-field test, and brains were harvested and sectioned. Cerebral cortex, hippocampus, amygdala, and entorhinal cortex sections were analyzed for phospho-tau (AT8) and microgliosis (Iba1). Hippocampal cellular density (H&E) was also assessed. PS19-Saline mice were hyperactive and less anxious compared to WT-Saline mice, and these behavioral phenotypes were significantly reduced in the PS19-cTfRMAb-EPO mice compared to the PS19-Saline mice. cTfRMAb-EPO significantly reduced AT8 load by ≥50% in all of the brain regions analyzed and microgliosis in the entorhinal cortex and amygdala compared to the PS19-Saline mice. Hippocampal pyramidal and granule cell layer density did not differ significantly between the PS19-cTfRMAb-EPO and PS19-Saline mice. This proof-of-concept study demonstrates the therapeutic effects of the BBB-penetrating cTfRMAb-EPO in PS19 mice.
Alzheimer's disease (AD) is a progressive decline in cognitive ability and behavior which eventually disrupts daily activities. AD has no cure and the progression rate varies unlikely. Among various causative factors, heavy metals are reported to be a significant hazard in AD pathogenesis. Metal‐induced neurodegeneration has been focused globally with thorough research to unravel the mechanistic insights in AD. Recently, heavy metals suggested to play an important role in epigenetic alterations which might provide evidential results on AD pathology. Epigenetic modifications are known to play towards novel therapeutic approaches in treating AD. Though many studies focus on epigenetics and heavy metal implications in AD, there is a lack of research on heavy metal influence on epigenetic toxicity in neurological disorders. The current review aims to elucidate the plausible role of cadmium (Cd), iron (Fe), arsenic (As), copper (Cu), and lithium (Li) metals on epigenetic factors and the increase in amyloid beta and tau phosphorylation in AD. Also, the review discusses the common methods of heavy metal detection to implicate in AD pathogenesis. Hence, from this review, we can extend the need for future research on identifying the mechanistic behavior of heavy metals on epigenetic toxicity and to develop diagnostic and therapeutic markers in AD.
Preterm infants are at high risk of brain injury. With more understanding of the preterm brain injury's pathogenesis, neuroscientists are looking for more effective methods to prevent and treat it, among which erythropoietin (Epo) is considered as a prime candidate. This review tries to clarify the possible mechanisms of Epo in preterm neuroprotection and summarize updated evidence considering Epo as a pharmacological neuroprotective strategy in animal models and clinical trials. To date, various animal models have validated that Epo is an anti-apoptotic, anti-inflammatory, anti-oxidant, anti-excitotoxic, neurogenetic, erythropoietic, angiogenetic, and neurotrophic agent, thus preventing preterm brain injury. However, although the scientific rationale and preclinical data for Epo's neuroprotective effect are promising, when translated to bedside, the results vary in different studies, especially in its long-term efficacy. Based on existing evidence, it is still too early to recommend Epo as the standard treatment for preterm brain injury.
Many studies of tauopathy use transgenic mice that overexpress the P301S mutant form of tau. Neuronal damage in these mice is associated with astrogliosis and induction of glial fibrillary acidic protein (GFAP) expression. GFAP-luc transgenic mice express firefly luciferase under the GFAP promoter, allowing bioluminescence to be measured non-invasively as a surrogate biomarker for astrogliosis. We bred double transgenic mice possessing both P301S and GFAP-luc cassettes and compared them to control mice bearing only the GFAP-luc transgene. We used serial bioluminescent images to define the onset and the time course of astrogliosis in these mice and this was correlated with the development of clinical deficit. Mice containing both GFAP-luc and P301S transgenes showed increased luminescence indicative of astroglial activation in the brain and spinal cord. Starting at 5 months old, the onset of clinical deterioration in these mice corresponded closely to the initial rise in the luminescent signal. Post mortem analysis showed the elevated luminescence was correlated with hyperphosphorylated tau deposition in the hippocampus of double transgenic mice. We used this method to determine the therapeutic effect of JM4 peptide [a small peptide immunomodulatory agent derived from human erythropoietin (EPO)] on double transgenic mice. JM4 treatment significantly decreased the intensity of luminescence, neurological deficit and hyperphosphorylated tau in mice with both the P301S and GFAP-luc transgenes. These findings indicate that bioluminescence imaging (BLI) is a powerful tool for quantifying GFAP expression in living P301S mice and can be used as a noninvasive biomarker of tau-induced neurodegeneration in preclinical therapeutic trials.
