Abstract
Background: Accumulating evidence suggests inhibiting neuroinflammation as a potential target in therapeutic or preventive strategies for Alzheimer's disease (AD). MAPK-activated protein kinase II (MK2), downstream kinase of p38 mitogen activated protein kinase (MAPK) p38 MAPK, was unveiled as a promising option for the treatment of AD. Increasing evidence points at MK2 as involved in neuroinflammatory responses. MMI-0100, a cell-penetrating peptide inhibitor of MK2, exhibits anti-inflammatory effects and is in current clinical trials for the treatment of pulmonary fibrosis. Therefore, it is important to understand the actions of MMI-0100 in neuroinflammation.Methods: The mouse memory function was evaluated using novel object recognition (NOR) and object location recognition (OLR) tasks. Brain hippocampus tissue samples were analyzed by quantitative PCR, Western blotting, and immunostaining. Near-infrared fluorescent and confocal microscopy experiments were used to detect the brain uptake and distribution after intranasal MMI-0100 application.Results: Central MMI-0100 was able to ameliorate the memory deficit induced by Aβ1−42 or LPS in novel object and location memory tasks. MMI-0100 suppressed LPS-induced activation of astrocytes and microglia, and dramatically decreased a series of pro-inflammatory cytokines such as TNF-α, IL-6, IL-1β, COX-2, and iNOS via inhibiting phosphorylation of MK2, but not ERK, JNK, and p38 in vivo and in vitro. Importantly, one of the reasons for the failure of macromolecular protein or peptide drugs in the treatment of AD is that they cannot cross the blood–brain barrier. Our data showed that intranasal administration of MMI-0100 significantly ameliorates the memory deficit induced by Aβ1−42 or LPS. Near-infrared fluorescent and confocal microscopy experiment results showed that a strong fluorescent signal, coming from mouse brains, was observed at 2 h after nasal applications of Cy7.5-MMI-0100. However, brains from control mice treated with saline or Cy7.5 alone displayed no significant signal.Conclusions: MMI-0100 attenuates Aβ1−42- and LPS-induced neuroinflammation and memory impairments via the MK2 signaling pathway. Meanwhile, these data suggest that the MMI-0100/MK2 system may provide a new potential target for treatment of AD.
Highlights
Alzheimer’s disease (AD), one of the most common neurodegenerative diseases, is characterized by progressive cognitive dysfunction, memory impairment, and behavioral changes
In the novel object recognition (NOR) and object location recognition (OLR) task, when the total exploration time (TET) was 10 s and memory was tested after 24 h, vehicle + vehicle-treated mice could discriminate the novel object or location from the familiar one, with the discrimination index (DI) (65.15% for NOR, 63.45% for OLR) being significantly higher than the 50% chance level (p < 0.01), but Aβ1−42 (i.c.v., 800 pmol) or LPS (i.c.v., 2 μg) treatment significantly disrupted memory; the average DI of this group (Aβ1−42: 50.96%, LPS: 49.82% for NOR; Aβ1−42: 48.04%, LPS: 49.62% for OLR) was significantly lower than that of vehicle + vehicle (∗∗p < 0.01 for Figure 2A, ∗∗∗p < 0.001 for Figure 2C, ∗∗p < 0.01 for Figure 3A and ∗p < 0.05 for Figure 3C)
The protein levels of IL-6, IL-1β, and tumor necrosis factor-α (TNF-α) were higher in the hippocampus of LPSor Aβ1−42-induced AD model mice, and MMI-0100 treatment markedly down-regulated the expression of IL-6, IL-1β, and TNF-α (Figure 6)
Summary
Alzheimer’s disease (AD), one of the most common neurodegenerative diseases, is characterized by progressive cognitive dysfunction, memory impairment, and behavioral changes. Increasing evidences suggest that microglia, the first line of defense and the resident macrophages of the brain in the central nervous system (CNS), play multiple roles in AD progression by clearing Aβ plaques and releasing proinflammatory mediators [e.g., tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β)], which might directly act on neurons to induce apoptosis [1, 4, 6, 7]. AD pathogenesis is not restricted to the neuronal compartment, but includes strong interactions with immunological mechanisms in the brain. Targeting of these immune mechanisms could lead to future therapeutic or preventive strategies for AD. Accumulating evidence suggests inhibiting neuroinflammation as a potential target in therapeutic or preventive strategies for Alzheimer’s disease (AD). MMI-0100, a cell-penetrating peptide inhibitor of MK2, exhibits anti-inflammatory effects and is in current clinical trials for the treatment of pulmonary fibrosis. It is important to understand the actions of MMI-0100 in neuroinflammation
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