Senile plaques, comprised of nanosized aggregates of amyloid-β (Aβ) peptides in the brain, are a pathological hallmark of Alzheimer's disease (AD). On the other hand, regular physical exercise is known to significantly reduce the risk of developing AD. Here, it is reported on the transformation and toxicity mitigation of Aβ amyloid aggregation by a spontaneous “corona” of β-endorphin, a major peptide hormone released upon exercise to suppress post-exercise pain. Given that both Aβ and β-endorphin co-localize extracellularly in the brain, it is postulated that β-endorphin may mitigate the toxicity of Aβ aggregation via direct molecular interactions, thereby contributing to an exercise-mediated reduction of AD risk. Combining biophysical characterizations in vitro with atomistic discrete molecular dynamics simulations in silico, a strong interaction is shown between β-endorphin and Aβ, where β-endorphins are located at the periphery to render a corona of their hetero-complexes with Aβ. Cell viability, immunofluorescence and western blotting assays further revealed that the corona shielded cellular exposure to Aβ aggregates and suppressed the toxicity of Aβ in vivo. This work offered a new molecular mechanism for the benefits of physical exercise, which may facilitate a rational design of future therapy and prevention strategies against AD and dementia.
Le Ma,Shiyu Peng,Jinbao Wei,Mengjing Zhao,Khalil Ali Ahmad,Jinghong Chen,Yong-Xiang Wang
Aim This study aimed to investigate the regulation of pain hypersensitivity induced by the spinal synaptic transmission mechanisms underlying interleukin (IL)-10 and glucagon-like peptide 1 receptor (GLP-1R) agonist exenatide-induced pain anti-hypersensitivity in neuropathic rats through spinal nerve ligations. Methods Neuropathic pain model was established by spinal nerve ligation of L5/L6 and verified by electrophysiological recording and immunofluorescence staining. Microglial expression of β-endorphin through autocrine IL-10- and exenatide-induced inhibition of glutamatergic transmission were performed by behavioral tests coupled with whole-cell recording of miniature excitatory postsynaptic currents (mEPSCs) and miniature inhibitory postsynaptic currents (mIPSCs) through application of endogenous and exogenous IL-10 and β-endorphin. Results Intrathecal injections of IL-10, exenatide, and the μ-opioid receptor (MOR) agonists β-endorphin and DAMGO inhibited thermal hyperalgesia and mechanical allodynia in neuropathic rats. Whole-cell recordings of bath application of exenatide, IL-10, and β-endorphin showed similarly suppressed enhanced frequency and amplitude of the mEPSCs in the spinal dorsal horn neurons of laminae II, but did not reduce the frequency and amplitude of mIPSCs in neuropathic rats. The inhibitory effects of IL-10 and exenatide on pain hypersensitive behaviors and spinal synaptic plasticity were totally blocked by pretreatment of IL-10 antibody, β-endorphin antiserum, and MOR antagonist CTAP. In addition, the microglial metabolic inhibitor minocycline blocked the inhibitory effects of IL-10 and exenatide but not β-endorphin on spinal synaptic plasticity. Conclusion This suggests that spinal microglial expression of β-endorphin mediates IL-10- and exenatide-induced inhibition of glutamatergic transmission and pain hypersensitivity via presynaptic and postsynaptic MORs in spinal dorsal horn.
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