Senile plaques stimulate microglia to release a neurotoxin found in Alzheimer brain

Giulian, Dana; Haverkamp, Lanny J.; Li, Jun; Karshin, W. L.; Yu, Jen; Tom, Deborah J; Li, Xia; Kirkpatrick, Joel B.

doi:10.1016/0197-0186(95)00067-i

Cited by 219 publications

(182 citation statements)

References 47 publications

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“…We propose that failure of microglia to stem the tide of neuronal degeneration and Aβ deposition in AD is the result of the concomitant overexpression of cytokines, such as IL-1, which not only set in motion neurodegenerative cascades but also induce further microglial activation. The inability of microglia to sufficiently clear debris in AD, including fDNA as shown here, may be responsible, at least in part, for the apparently continuous activation of microglia, overexpressing IL-1, in AD, thus ensuring a constant source of cytokines and other factors that foster neurodegeneration (Barger and Harmon, 1997;Giulian et al, 1995;Li et al, 2000;Meda et al, 1995;Paresce et al, 1996). Our finding that some microglia had TUNEL-positive cytoplasm as well as TUNEL positive-nuclei suggests that activation of microglia, together with the act of taking up fDNA, leads to the death of microglia.…”

Section: Discussionmentioning

confidence: 97%

“…Our in vitro experiments identify mechanisms involved in microglial internalization of fDNA. This uptake was via multiple scavenger receptor classes, concomitantly activating microglia and inducing excessive expression of IL-1, a cytokine known to regulate several neurodegenerative cascades, including phosphorylation of tau, decreased production of synaptophysin (Li et al, 2003), and alterations in neurotransmitter systems and cell survival (Barger and Basile, 2001;Giulian et al, 1995;Li et al, 2000). Each of these IL-1-driven events is important in Alzheimer pathogenesis (Griffin and Mrak, 2002).…”

Section: Discussionmentioning

confidence: 99%

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Microglial activation by uptake of fDNA via a scavenger receptor

Liu

et al. 2004

Journal of Neuroimmunology

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The fate of the fragmented DNA (fDNA) observed in neuronal nuclei in Alzheimer brain is unknown. However, its fate is suggested as fDNA is found in the cytoplasm of adjacent activated microglia. After a brief incubation with fDNA, approximately 70% of microglia had fDNA in their cytoplasm, were activated, and overexpressed interleukin-1β. Microglial activation enhanced uptake whereas blocking scavenger receptors suppressed this uptake. These results suggest that the brain rids itself of fDNA from dying neurons through microglial uptake, activation, and overexpression of IL-1. Such overexpression of IL-1 in Alzheimer brain has been linked to Alzheimer pathogenesis.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Microglial activation by uptake of fDNA via a scavenger receptor

Liu

et al. 2004

Journal of Neuroimmunology

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“…49 Microglia are the primary cell type to respond to injury in the CNS. Microglial activation in response to a stimulus includes proliferation, recruitment, and differentiation into phagocytic cells.…”

Section: Discussionmentioning

confidence: 99%

Microglial and Astrocyte Chemokines Regulate Monocyte Migration through the Blood-Brain Barrier in Human Immunodeficiency Virus-1 Encephalitis

Persidsky

Ghorpade

Rasmussen

et al. 1999

The American Journal of Pathology

269

196

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The numbers of immune-activated brain mononuclear phagocytes (MPs) affect the progression of human immunodeficiency virus (HIV)-1-associated dementia (HAD). Such MPs originate , in measure , from a pool of circulating monocytes. To address the mechanism(s) for monocyte penetration across the bloodbrain barrier (BBB) , we performed cross-validating laboratory , animal model , and human brain tissue investigations into HAD pathogenesis. First , an artificial BBB was constructed in which human brain microvascular endothelial and glial cells-astrocytes, microglia , and/or monocyte-derived macrophages (MDM)-were placed on opposite sides of a matrixcoated porous membrane. Second , a SCID mouse model of HIV-1 encephalitis (HIVE) was used to determine in vivo monocyte blood-to-brain migration. Third , immunohistochemical analyses of human HIVE tissue defined the relationships between astrogliosis , activation of microglia , virus infection, monocyte brain infiltration , and ␤-chemokine expression. The results , taken together , showed that HIV-1-infected microglia increased monocyte migration through an artificial BBB 2 to 3.5 times more than replicate numbers of MDM. In the HIVE SCID mice, a marked accumulation of murine MDM was found in areas surrounding virus-infected human microglia but not MDM. For human HIVE , microglial activation and virus infection correlated with astrogliosis, monocyte transendothelial migration , and ␤-chemokine expression. Pure cultures of virus-infected and activated microglia or astrocytes exposed to microglial conditioned media produced significant quantities of ␤-chemokines. We conclude that microglial activation alone and/or through its interactions with astrocytes induces ␤-chemokine-mediated monocyte migration in HAD. (Am J Pathol 1999, 155:1599 -1611)

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“…This eventually leads to the death of smooth muscle cells and endothelial cells in the vicinity of amyloid deposits (Vonsattel et al, 1991). The presence of Aβ deposits in the vasculature can also lead to proinflammatory responses including microglia/macrophage activation (Giulian et al, 1995) and complement activation (McGeer et al, 1989). Although Aβ peptide can be directly toxic to HCSMC (Davis et al, 1999;Wilhelmus et al, 2005), the involvement of other mechanisms in mediating cerebrovascular damage, including inflammatory processes, has been indicated (Miao et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Human postmortem brain-derived cerebrovascular smooth muscle cells express all genes of the classical complement pathway: A potential mechanism for vascular damage in cerebral amyloid angiopathy and Alzheimer's disease

Walker

Dalsing-Hernandez

Lue

2008

Microvascular Research

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Deposition of amyloid around blood vessels, known as cerebral amyloid angiopathy (CAA), is a major pathological feature found in the majority of Alzheimer's disease (AD) cases, and activated complement fragments have been detected on CAA deposits in AD brains. In this study, we demonstrate for the first time that human cerebrovascular smooth muscle cells (HCSMC) isolated from cortical vessels derived from postmortem brains can express mRNAs for complement genes C1qB, C1r, C1s, C2, C3, C4, C5, C6, C7, C8 and C9, the components of the classical complement pathway. Secretion of the corresponding complement proteins for these genes was also demonstrated, except for C1q and C5. Of particular significance was the observation that treatment of HCSMC with aggregated amyloid beta (Aβ)1-42 increased expression of complement C3 mRNA and increased release of C3 protein. Aβ treatment of HCSMC also increased expression of C6 mRNA. Interferon-γ induced expression and release of complement C1r, C1s, C2 and C4. As HCSMC are closely associated with Aβ deposits in vessels in the brain, their production of complement proteins could amplify the proinflammatory effects of amyloid in the perivascular environment, further compromising brain vascular integrity.

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Senile plaques stimulate microglia to release a neurotoxin found in Alzheimer brain

Cited by 219 publications

References 47 publications

Microglial activation by uptake of fDNA via a scavenger receptor

Microglial activation by uptake of fDNA via a scavenger receptor

Microglial and Astrocyte Chemokines Regulate Monocyte Migration through the Blood-Brain Barrier in Human Immunodeficiency Virus-1 Encephalitis

Human postmortem brain-derived cerebrovascular smooth muscle cells express all genes of the classical complement pathway: A potential mechanism for vascular damage in cerebral amyloid angiopathy and Alzheimer's disease

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