Microglial derived tumor necrosis factor-α drives Alzheimer's disease-related neuronal cell cycle events

Bhaskar, Kiran; Maphis, Nicole; Xu, Guixiang; Varvel, Nicholas H.; Kokiko-Cochran, Olga N.; Weick, Jason P.; Staugaitis, Susan M.; Cardona, Astrid E.; Ransohoff, Richard M.; Herrup, Karl; Lamb, Bruce T.

doi:10.1016/j.nbd.2013.10.007

Cited by 125 publications

(79 citation statements)

References 88 publications

(108 reference statements)

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“…Overall, cytokine expression was higher in R1.40 mice than Non-Tg mice and cytokine expression increased at 120 DPI compared to 3 DPI. This finding is consistent with previous studies showing that cytokine expression is enhanced in R1.40 mice at six months of age 65 This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.…”

Section: Discussionsupporting

confidence: 92%

Altered Neuroinflammation and Behavior after Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease

Kokiko-Cochran

Ransohoff

Veenstra

et al. 2016

Journal of Neurotrauma

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Traumatic brain injury (TBI) has acute and chronic sequelae, including an increased risk for the development of Alzheimer's disease (AD). TBI-associated neuroinflammation is characterized by activation of brain-resident microglia and infiltration of monocytes; however, recent studies have implicated beta-amyloid as a major manipulator of the inflammatory response. To examine neuroinflammation after TBI and development of AD-like features, these studies examined the effects of TBI in the presence and absence of beta-amyloid. The R1.40 mouse model of cerebral amyloidosis was used, with a focus on time points well before robust AD pathologies. Unexpectedly, in R1.40 mice, the acute neuroinflammatory response to TBI was strikingly muted, with reduced numbers of CNS myeloid cells acquiring a macrophage phenotype and decreased expression of inflammatory cytokines. At chronic time points, macrophage activation substantially declined in non-Tg TBI mice; however, it was relatively unchanged in R1.40 TBI mice. The persistent inflammatory response coincided with significant tissue loss between 3 and 120 days post-injury in R1.40 TBI mice, which was not observed in non-Tg TBI mice. Surprisingly, inflammatory cytokine expression was enhanced in R1.40 mice compared with non-Tg mice, regardless of injury group. Although R1.40 TBI mice demonstrated task-specific deficits in cognition, overall functional recovery was similar to non-Tg TBI mice. These findings suggest that accumulating beta-amyloid leads to an altered post-injury macrophage response at acute and chronic time points. Together, these studies emphasize the role of post-injury neuroinflammation in regulating long-term sequelae after TBI and also support recent studies implicating beta-amyloid as an immunomodulator.

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Section: Discussionsupporting

confidence: 92%

Altered Neuroinflammation and Behavior after Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease

Kokiko-Cochran

Ransohoff

Veenstra

et al. 2016

Journal of Neurotrauma

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“…Importantly, the activation of MAPK signalling occurs via cellular stress arising from inflammatory cytokines such as TNFα [46] or Aβ plaques [47]. We showed that elevated phosphorylation of Erk1/2 in the neocortex and brainstem is associated with Aβ plaques and increased TNFα expression, respectively, as well as increased apoptosis-inducing caspase3 levels in the brainstem.…”

Section: Discussionmentioning

confidence: 99%

An integrated proteomics approach shows synaptic plasticity changes in an APP/PS1 Alzheimer's mouse model

et al. 2016

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The aim of this study was to elucidate the molecular signature of Alzheimer's disease-associated amyloid pathology.We used the double APPswe/PS1ΔE9 mouse, a widely used model of cerebral amyloidosis, to compare changes in proteome, including global phosphorylation and sialylated N-linked glycosylation patterns, pathway-focused transcriptome and neurological disease-associated miRNAome with age-matched controls in neocortex, hippocampus, olfactory bulb and brainstem. We report that signalling pathways related to synaptic functions associated with dendritic spine morphology, neurite outgrowth, long-term potentiation, CREB signalling and cytoskeletal dynamics were altered in 12 month old APPswe/PS1ΔE9 mice, particularly in the neocortex and olfactory bulb. This was associated with cerebral amyloidosis as well as formation of argyrophilic tangle-like structures and microglial clustering in all brain regions, except for brainstem. These responses may be epigenetically modulated by the interaction with a number of miRNAs regulating spine restructuring, Aβ expression and neuroinflammation.We suggest that these changes could be associated with development of cognitive dysfunction in early disease states in patients with Alzheimer's disease.

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“…103 Clustering of activated microglia and astrocytes have been reported surrounding A plaques and correlated with elevated inflammatory cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor-. 104,105 Furthermore, peripheral monocytes/macrophages are capable of clearing vascular A . 106 In an in vivo multi-photon imaging study, circulating monocytes have been shown to enter luminal walls of A -positive veins and carry amyloid back into the bloodstream.…”

Section: Neuroinflammationmentioning

confidence: 99%

The neuropathology and cerebrovascular mechanisms of dementia

Raz

Knoefel

Bhaskar

2015

J Cereb Blood Flow Metab

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366

284

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The prevalence of dementia is increasing in our aging population at an alarming rate. Because of the heterogeneity of clinical presentation and complexity of disease neuropathology, dementia classifications remain controversial. Recently, the National Plan to address Alzheimer's Disease prioritized Alzheimer's disease-related dementias to include: Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia, vascular dementia, and mixed dementias. While each of these dementing conditions has their unique pathologic signature, one common etiology shared among all these conditions is cerebrovascular dysfunction at some point during the disease process. The goal of this comprehensive review is to summarize the current findings in the field and address the important contributions of cerebrovascular, physiologic, and cellular alterations to cognitive impairment in these human dementias. Specifically, evidence will be presented in support of small-vessel disease as an underlying neuropathologic hallmark of various dementias, while controversial findings will also be highlighted. Finally, the molecular mechanisms shared among all dementia types including hypoxia, oxidative stress, mitochondrial bioenergetics, neuroinflammation, neurodegeneration, and bloodbrain barrier permeability responsible for disease etiology and progression will be discussed.

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Microglial derived tumor necrosis factor-α drives Alzheimer's disease-related neuronal cell cycle events

Cited by 125 publications

References 88 publications

Altered Neuroinflammation and Behavior after Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease

Altered Neuroinflammation and Behavior after Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease

An integrated proteomics approach shows synaptic plasticity changes in an APP/PS1 Alzheimer's mouse model

The neuropathology and cerebrovascular mechanisms of dementia

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