Downregulation of TREM2 expression exacerbates neuroinflammatory responses through TLR4-mediated MAPK signaling pathway in a transgenic mouse model of Alzheimer's disease.

Activation of glial cells and neuroinflammation play an important role in the onset and development of Alzheimer's disease (AD). Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia-specific receptor in the brain that is involved in regulating neuroinflammation. However, the precise effects of TREM2 on neuroinflammatory responses and its underlying molecular mechanisms in AD have not been studied in detail. Here, we employed a lentiviral-mediated strategy to downregulation of TREM2 expression on microglia in the brain of APPswe/PS1dE9 (APP/PS1) transgenic mice and BV2 cells. Our results showed that downregulation of TREM2 significantly aggravated AD-related neuropathology including Aß accumulation, peri-plaque microgliosis and astrocytosis, as well as neuronal and synapse-associated proteins loss, which was accompanied by a decline in cognitive ability. The further mechanistic study revealed that downregulation of TREM2 expression initiated neuroinflammatory responses through toll-like receptor 4 (TLR4)-mediated mitogen-activated protein kinase (MAPK) signaling pathway and subsequent stimulating the production of pro-inflammatory cytokines in vivo and in vitro. Moreover, blockade of p38, JNK, and ERK1/2 inhibited the release of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6) induced by Aß1-42 in TREM2-knocked down BV2 cells. Taken together, these findings indicated that TREM2 might be a potential therapeutic target for AD and other neuroinflammation-related diseases.

TREM2 overexpression rescues cognitive deficits in APP/PS1 transgenic mice by reducing neuroinflammation via the JAK/STAT/SOCS signaling pathway.

Overactivated microglia and neuroinflammation are considered to play a crucial role in the progression of Alzheimer's disease (AD). Triggering receptor expressed on myeloid cells-2 (TREM2), a type I transmembrane receptor, expressed uniquely by microglia in the brain, is involved in the neuroinflammatory responses of AD. In this study, to further explore the precise effects of TREM2 on neuroinflammation and the underlying mechanisms in AD, we employed a lentiviral-mediated strategy to overexpress TREM2 in the brain of APPswe/PS1dE9 (APP/PS1) transgenic mice and cultured BV2 cells. Our results showed that TREM2 overexpression rescued cognitive deficits, decreased ß-amyloid (Aß) plaques deposition, reduced synaptic and neuronal loss, as well as ameliorated neuroinflammation. The mechanistic study revealed that these protective effects were likely attributed to inhibition of neuroinflammatory responses through the JAK/STAT/SOCS signaling pathway and subsequent attenuation of pro-inflammatory cytokines. Furthermore, suppression of neuroinflammation might be ascribed to activation of the M2 microglia, as the levels of M2 phenotype markers Arg-1, IL-10 and Ym1 were markedly increased. Similarly, overexpression of TREM2 in BV2 cells also promoted M2 polarization and led to the alleviation of M1 microglial inflammatory responses through JAK/STAT/SOCS signaling pathway, suggesting that TREM2 is an important factor in shifting the microglia from M1 to M2 phenotype. Taken together, our results further provide insights into the role of TREM2 in AD pathogenesis and highlight TREM2 as a potential target against AD.

Silencing of LRP1 Exacerbates Inflammatory Response Via TLR4/NF-κB/MAPKs Signaling Pathways in APP/PS1 Transgenic Mice.

Activation of glial cells (including microglia and astrocytes) appears central to the initiation and progression of neuroinflammation in Alzheimer's disease (AD). The low-density lipoprotein receptor-related protein 1 (LRP1) is a major receptor for amyloid-ß (Aß), which plays a critical role in AD pathogenesis. LRP1 regulates inflammatory response by modulating the release of pro-inflammatory cytokines and phagocytosis. However, the effects of LRP1 on microglia- and astrocytic cell-mediated neuroinflammation and their underlying mechanisms in AD remain unclear. Therefore, using APP/PS1 transgenic mice, we found that LRP1 is downregulated during disease progression. Silencing of brain LRP1 markedly exacerbated AD-related neuropathology including Aß deposition, neuroinflammation, and synaptic and neuronal loss, which was accompanied by a decline in spatial cognitive ability. Further mechanistic study revealed that silencing of LRP1 initiated neuroinflammation by increasing microgliosis and astrogliosis, enhancing pro-inflammatory cytokine production, and regulating toll-like receptor 4 (TLR4)-mediated activation of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. Taken together, these findings indicated that LRP1 suppresses microglia and astrocytic cell activation by modulating TLR4/NF-κB/MAPK signaling pathways. Our results further provide insights into the role of LRP1 in AD pathogenesis and highlight LRP1 as a potential therapeutic target for the treatment of AD.

Tanshinone IIA ameliorates cognitive deficits by inhibiting endoplasmic reticulum stress-induced apoptosis in APP/PS1 transgenic mice.

Our previous data indicated that tanshinone IIA (tan IIA) improves learning and memory in a mouse model of Alzheimer's disease (AD) induced by streptozotocin via restoring cholinergic function, attenuating oxidative stress and blocking p38 MAPK signal pathway activation. This study aims to estimate whether tan IIA inhibits endoplasmic reticulum (ER) stress-induced apoptosis to prevent cognitive decline in APP/PS1 transgenic mice. Tan IIA (10 mg/kg and 30 mg/kg) was intraperitoneally administered to the six-month-old APP/PS1 mice for 30 consecutive days. ß-amyloid (Aß) plaques were measured by immunohistochemisty and Thioflavin S staining, apoptotic cells were observed by TUNEL, ER stress markers and apoptosis signaling proteins were investigated by western blotting and RT-PCR. Our results showed that tan IIA significantly ameliorates cognitive deficits and improves spatial learning ability of APP/PS1 mice in the nest-building test, novel object recognition test and Morris water maze test. Furthermore, tan IIA significantly reduced the deposition of Aß plaques and neuronal apoptosis, and markedly prevented abnormal expression of glucose regulated protein 78 (GRP78), initiation factor 2α (eIF2α), inositol-requiring enzyme 1α (IRE1α), activating transcription factor 6 (ATF6), as well as suppressed the activation of C/EBP homologous protein (CHOP) and c-Jun N-terminal kinase (JNK) pathways in the parietal cortex and hippocampus. Moreover, tan IIA induced an up-regulation of the Bcl-2/Bax ratio and down-regulation of caspase-3 protein activity. Taken together, the above findings indicated that tan IIA improves learning and memory through attenuating Aß plaques deposition and inhibiting ER stress-induced apoptosis. These results suggested that tan IIA might become a promising therapeutic candidate drug against AD.