Silencing of TREM2 exacerbates tau pathology, neurodegenerative changes, and spatial learning deficits in P301S tau transgenic mice

Jiang, Teng; Tan, Lan; Zhu, Xi-Chen; Zhou, Junshan; Cao, Lei; Tan, Meng-Shan; Wang, Hui-Fu; Chen, Qi; Yu, Jin‐Tai

doi:10.1016/j.neurobiolaging.2015.08.019

Cited by 90 publications

(88 citation statements)

References 49 publications

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“…Furthermore, phosphorylation of tau is attenuated in female APP/ PSEN1 mice with loss of DAP12. In contrast, silencing of brain TREM2 exacerbates tau pathology in P301S tau transgenic mice, associated with neuroinflammationinduced overactivation of tau kinases, such as cyclin dependent kinase 5 (CDK5) and glycogen synthase kinase 3 beta (GSK3B) (21). Thus, the absence of either DAP12 or TREM2 produces apparently opposing effects on progression of AD pathology in mouse models of AD.…”

Section: Resultsmentioning

confidence: 99%

Alzheimer's disease pathology in Nasu-Hakola disease brains

Satoh

Kino

Yanaizu

et al. 2018

IRDR

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Section: Resultsmentioning

confidence: 99%

Alzheimer's disease pathology in Nasu-Hakola disease brains

Satoh

Kino

Yanaizu

et al. 2018

IRDR

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“…Mounting evidence indicates that microglia-generated proinflammatory cytokines (e.g., IL-6 and TNF-α) are responsible for neuronal and synaptic losses, whereas anti-inflammatory therapies can effectively attenuate neuronal and synaptic damage and improve cognitive deficits in animal models of neuroinflammation and aging [45, 46]. TREM2 silencing led to the exacerbation of neuronal and synaptic losses in the cerebral cortex and hippocampus of P301S mice [47]. Surgery-induced downregulation of synaptophysin in the hippocampus contributed to spatial cognitive dysfunctions in this study.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of TREM2 Ameliorates Neuroinflammatory Responses and Improves Cognitive Deficits Triggered by Surgical Trauma in Appswe/PS1dE9 Mice

Jiang

et al. 2018

Cell Physiol Biochem

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Background/Aims: TREM2 plays a crucial role in modulating microglial function through interaction with DAP12, the adapter for TREM2. Emerging evidence has demonstrated that TREM2 could suppress neuroinflammatory responses by repression of microglia-mediated cytokine production. This study investigated the potential role of TREM2 in surgery-induced cognitive deficits and neuroinflammatory responses in wild-type (WT) and APPswe/PS1dE9 mice. Methods: Adult APPswe/PS1dE9 transgenic male mice (a classic transgenic model of Alzheimer’s disease, 3 months old) and their age-matched WT mice received intracerebral lentiviral particles encoding the mouse TREM2 gene and then were subjected to partial hepatectomy at 1 month after the lentiviral particle injection. The behavioral changes were evaluated with an open-field test and Morris water maze test on postoperative days 3, 7, and 14. Hippocampal TREM2, DAP12, and interleukin (IL)-1β were measured at each time point. Ionized calcium-binding adapter molecule 1 (Iba-1), microglial M2 phenotype marker Arg1, synaptophysin, tau hyperphosphorylation (T396), and glycogen synthase kinase-3β (GSK-3β) were also examined in the hippocampus. Results: Surgical trauma induced an exacerbated cognitive impairment and enhanced hippocampal IL-1β expression in the transgenic mice on postoperative days 3 and 7. A corresponding decline in the levels of TREM2 was also found on postoperative days 3, 7, and 14. Overexpression of TREM2 downregulated the levels of IL-1β, ameliorated T396 expression, inhibited the activity of GSK-3β, and improved sickness behavior. Increased Arg1 expression and a high level of synaptophysin were also observed in the transgenic mice following TREM2 overexpression. Conclusion: The downregulation of TREM2 exacerbated surgery-induced cognitive deficits and exaggerated neuroinflammatory responses in this rodent model. Overexpression of TREM2 potentially attenuated these effects by decreasing the associated production of proinflammatory cytokines, inhibiting tau hyperphosphorylation, and enhancing synaptophysin expression.

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“…TREM2 deficiency eliminated plaque-associated CD45 hi LyC + myeloid cells, leading to reduced inflammation and AD-like pathology in these mice (155); however, TREM2-expressing myeloid cells were enriched in microglia processes contacting amyloid deposits in AD mice, and TREM2 deletion resulted in less compact plaques and increased dystrophic neurites. Similarly, TREM2 silencing in P301S mice increased tau pathology and synapse loss and enhanced the proinflammatory cytokine levels in the brain (156). A recent report indicated that the opposing results from previous work might reflect a disease progression-dependent influence of TREM2 deficiency on AD pathology.…”

Section: Trem2mentioning

confidence: 93%