The five melanocortin receptors (MC1R–MC5R) are involved in numerous biological pathways, including steroidogenesis, pigmentation, and food intake. In particular, MC3R and MC4R knockout mice suggest that the MC3R and MC4R regulate energy homeostasis in a non-redundant manner. While MC4R-selective agonists have been utilized as appetite modulating agents, the lack of MC3R-selective agonists has impeded progress in modulating this receptor in vivo. In this study, the (pI)DPhe position of the tetrapeptide Ac-His-Arg-(pI)DPhe-Tic-NH2 (an MC3R agonist/MC4R antagonist ligand) was investigated with a library of 12 compounds. The compounds in this library were found to have higher agonist efficacy and potency at the mouse (m) MC3R compared to the MC4R, indicating that the Arg-DPhe motif preferentially activates the mMC3R over the mMC4R. This observation may be used in the design of new MC3R-selective ligands, leading to novel probe and therapeutic lead compounds that will be useful for treating metabolic disorders.
MHCII molecules, expressed by professional antigen-presenting cells (APCs) such as T cells and B cells, are hypothesized to play a key role in the response of cellular immunity to α-synuclein (α-syn). However, the role of cellular immunity in the neuroanatomic transmission of α-syn pre-formed fibrillar (PFF) seeds is undetermined. To illuminate whether cellular immunity influences the transmission of α-syn seeds from the periphery into the CNS, we injected preformed α-syn PFFs in the hindlimb of the Line M83 transgenic mouse model of synucleinopathy lacking MhcII. We showed that a complete deficiency in MhcII accelerated the appearance of seeded α-syn pathology and shortened the lifespan of the PFF-seeded M83 mice. To characterize whether B-cell and T-cell inherent MhcII function underlies this accelerated response to PFF seeding, we next injected α-syn PFFs in Rag1−/− mice which completely lacked these mature lymphocytes. There was no alteration in the lifespan or burden of endstage α-syn pathology in the PFF-seeded, Rag1-deficient M83+/− mice. Together, these results suggested that MhcII function on immune cells other than these classical APCs is potentially involved in the propagation of α-syn in this model of experimental synucleinopathy. We focused on microglia next, finding that while microglial burden was significantly upregulated in PFF-seeded, MhcII-deficient mice relative to controls, the microglial activation marker Cd68 was reduced in these mice, suggesting that these microglia were not responsive. Additional analysis of the CNS showed the early appearance of the neurotoxic astrocyte A1 signature and the induction of the Ifnγ-inducible anti-viral response mediated by MhcI in the MhcII-deficient, PFF-seeded mice. Overall, our data suggest that the loss of MhcII function leads to a dysfunctional response in non-classical APCs and that this response could potentially play a role in determining PFF-induced pathology. Collectively, our results identify the critical role of MhcII function in synucleinopathies induced by α-syn prion seeds.
Background Alzheimer’s disease (AD) is a neurodegenerative disease characterized pathologically by intracellular neurofibrillary tangles (NFT), extracellular amyloid β (Aβ) plaques, and neuroinflammation. Interleukin 10 (IL10) is an anti‐inflammatory cytokine released by immune and glial cells. Since IL10 is anti‐inflammatory, it has the potential to be a therapy for neurodegenerative diseases with an inflammatory component. However, contrary to what we expected, an earlier study from our group showed that overexpression of IL10 actually led to an increase in Aβ plaque burden in a mouse model of Aβ plaques. Therefore, we proposed to assess the effect of overexpression of the soluble extracellular portion of the IL10 receptor (sIL10R) on disease pathogenesis in both an Aβ mouse model and tau mouse models. The premise was that this soluble form of the receptor would attenuate IL10 signaling, thus reversing its anti‐inflammatory properties. Method To investigate the effect of sIL10R expression on Aβ plaques, we used adeno‐associated virus (AAV) to express sIL10R in neonatal TgCRND8 mice and aged them 3 or 6 months. We next investigated whether sIL10R also affected tau pathology in two tau mouse models: a slowly‐progressing spinal cord tauopathy model (JNPL3) and a rapid model with primarily cortical and hippocampal tauopathy (rTg4510). Result Assessment of Aβ plaque burden revealed decreased Aβ plaque load in the younger TgCRND8 cohort, but this effect was not observed in the 6 month old mice. We observed a significant reduction of phosphorylated tau and a trend towards reduced p62 levels in the JNPL3 mice. However, we did not observe changes in phosphorylated tau or p62 levels in 4 month old or 6 month old rTg4510 mice. Quantification of neuroinflammatory markers in APP and tau mouse models showed distinct patterns of neuroinflammation specific to each model. Conclusion Our study demonstrates that a decoy receptor may be a potential therapeutic for Alzheimer’s disease and that attenuation of Aβ and tau pathogenesis may occur at different rates and at different disease stages. Future experiments will center around characterizing possible mechanisms underlying these changes.
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