NSAIDs prevent, but do not reverse, neuronal cell cycle reentry in a mouse model of Alzheimer disease

Varvel, Nicholas H.; Bhaskar, Kiran; Kounnas, Maria Z.; Wagner, Steven L.; Yang, Yan; Lamb, Bruce T.; Herrup, Karl

doi:10.1172/jci39716

Cited by 110 publications

(96 citation statements)

References 61 publications

(89 reference statements)

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“…Furthermore, TREM2 overexpression in the brain of APPswe/PS1dE9 mice significantly attenuated neuronal and synaptic losses, which was accompanied by an improvement in spatial cognitive function. The neurotoxicity of Ab and proinflammatory cytokines led to the neuronal and synaptic damage in cellular and animal models of AD (Calkins and Reddy, 2011;Gouras et al, 2010;Kapadia and Sakic, 2011), which could be effectively prevented by Ab-targeting therapy or anti-inflammatory treatment (Adolfsson et al, 2012;Varvel et al, 2009). On consideration of this evidence, the attenuation of neuronal and synaptic losses by TREM2 overexpression was likely attributed to the amelioration of Ab neuropathology and neuroinflammation in this scenario.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of TREM2 Ameliorates Neuropathology and Rescues Spatial Cognitive Impairment in a Transgenic Mouse Model of Alzheimer’s Disease

Jiang

Tan

Zhu

et al. 2014

Neuropsychopharmacol

230

205

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Triggering receptor expressed on myeloid cells 2 (TREM2) gene is a recently identified susceptibility gene for Alzheimer's disease (AD), as its low-frequency variants increase the risk of this disease with an odds ratio similar to that of an APOE e4 allele. To date, the expression and biologic functions of TREM2 under AD context remain largely unknown. Using APPswe/PS1dE9 mice, a transgenic model of AD, we showed that TREM2 was upregulated in microglia during disease progression. For the first time, we provided in vitro and in vivo evidence that this upregulation was attributed to the increased amyloid-b (Ab) 1-42 levels in the brain. By knockdown and overexpression of TREM2 in cultured primary microglia, we revealed that TREM2 modulated microglial functions under AD context, as it facilitated Ab 1-42 phagocytosis and inhibited Ab 1-42 -triggered proinflammatory responses. Meanwhile, this modulation was dependent on DAP12, the adapter protein of TREM2. More importantly, overexpression of TREM2 in the brain of APPswe/PS1dE9 mice markedly ameliorated AD-related neuropathology including Ab deposition, neuroinflammation, and neuronal and synaptic losses, which was accompanied by an improvement in spatial cognitive functions. Taken together, our data suggest that the upregulation of TREM2 serves as a compensatory response to Ab 1-42 and subsequently protects against AD progression by modulation of microglia functions. These findings provide insights into the role of TREM2 in AD pathogenesis, and highlight TREM2 as a potential therapeutic target for this disease.

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Section: Discussionmentioning

confidence: 99%

Upregulation of TREM2 Ameliorates Neuropathology and Rescues Spatial Cognitive Impairment in a Transgenic Mouse Model of Alzheimer’s Disease

Jiang

Tan

Zhu

et al. 2014

Neuropsychopharmacol

230

205

View full text Add to dashboard Cite

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“…Cite this article as Cold Spring Harb Perspect Biol 2015;7:a021287 sion associated with glial response and aberrant cell-cycle changes, as described in other brain regions (Yang et al 2001;Varvel et al 2009). …”

Section: Adult Neurogenesis In Neurodegenerative Diseasesmentioning

confidence: 99%

Adult Neurogenesis in Neurodegenerative Diseases: Figure 1.

Winner¹,

Winkler

2015

Cold Spring Harb Perspect Biol

255

207

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“…A role for inflammation in the pathogenesis of Alzheimer's disease (AD) is suggested by epidemiological studies that have reported a decreased incidence of AD in patients treated with nonsteroidal anti-inflammatory drugs (1,2); these findings are supported by evidence of preventative effects of these drugs in animal models of AD (3). Whereas the classical characteristics of AD are the presence of amyloid-b (Ab) plaques and neurofibrillary tangles, together with selective neuronal loss, there is also evidence of innate immune activation in AD, with activation of microglia, the primary resident immune cell of the CNS.…”

mentioning

confidence: 99%

IFN-γ Production by Amyloid β–Specific Th1 Cells Promotes Microglial Activation and Increases Plaque Burden in a Mouse Model of Alzheimer’s Disease

Browne

McQuillan

McManus

et al. 2013

The Journal of Immunology

244

178

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Alzheimer’s disease (AD) is characterized by the presence of amyloid-β (Aβ)–containing plaques, neurofibrillary tangles, and neuronal loss in the brain. Inflammatory changes, typified by activated microglia, particularly adjacent to Aβ plaques, are also a characteristic of the disease, but it is unclear whether these contribute to the pathogenesis of AD or are a consequence of the progressive neurodegenerative processes. Furthermore, the factors that drive the inflammation and neurodegeneration remain poorly understood. CNS-infiltrating T cells play a pivotal role in the pathogenesis of multiple sclerosis, but their role in the progression of AD is still unclear. In this study, we examined the role of Aβ-specific T cells on Aβ accumulation in transgenic mice that overexpress amyloid precursor protein and presenilin 1 (APP/PS1). We found significant infiltration of T cells in the brains of APP/PS1 mice, and a proportion of these cells secreted IFN-γ or IL-17. Aβ-specific CD4 T cells generated by immunization with Aβ and a TLR agonist and polarized in vitro to Th1-, Th2-, or IL-17–producing CD4+ T cells, were adoptively transferred to APP/PS1 mice at 6 to 7 mo of age. Assessment of animals 5 wk later revealed that Th1 cells, but not Th2 or IL-17–producing CD4+ T cells, increased microglial activation and Aβ deposition, and that these changes were associated with impaired cognitive function. The effects of Th1 cells were attenuated by treatment of the APP/PS1 mice with an anti–IFN-γ Ab. Our study suggests that release of IFN-γ from infiltrating Th1 cells significantly accelerates markers of diseases in an animal model of AD.

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NSAIDs prevent, but do not reverse, neuronal cell cycle reentry in a mouse model of Alzheimer disease

Abstract: Ectopic cell cycle events (CCEs) mark vulnerable neuronal populations in human

Cited by 110 publications

References 61 publications

Upregulation of TREM2 Ameliorates Neuropathology and Rescues Spatial Cognitive Impairment in a Transgenic Mouse Model of Alzheimer’s Disease

Upregulation of TREM2 Ameliorates Neuropathology and Rescues Spatial Cognitive Impairment in a Transgenic Mouse Model of Alzheimer’s Disease

Adult Neurogenesis in Neurodegenerative Diseases: Figure 1.

IFN-γ Production by Amyloid β–Specific Th1 Cells Promotes Microglial Activation and Increases Plaque Burden in a Mouse Model of Alzheimer’s Disease

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