Microglial Response to Transient Focal Cerebral Ischemia: An Immunocytochemical Study on the Rat Cerebral Cortex Using Anti-Phosphotyrosine Antibody

Korematsu, Kojiro; Goto, Satoshi; Saijo, Nagahiro; Ushio, Yukitaka

doi:10.1038/jcbfm.1994.103

Cited by 53 publications

(29 citation statements)

References 27 publications

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“…No such aggregations of Mac-1-positive microglia were observed in nontransgenic littermates (Figure 1B). Similarly, using an antibody to phosphotyrosine, which is a specific marker for microglia in the central nervous system, 20,21 clusters of intensely stained microglia were observed in transgenic mice but not in littermate controls (Figure 1, C and D). In contrast to antiMac-1 staining, antibodies to phosphotyrosine revealed only weak staining of microglia in nontransgenic control mice ( Figure 1D).…”

Section: Activated Microglia Associated With Congophilic Plaques But mentioning

confidence: 85%

Association of Microglia with Amyloid Plaques in Brains of APP23 Transgenic Mice

Stalder¹,

Phinney²,

Probst³

et al. 1999

The American Journal of Pathology

305

201

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Microglia are a key component of the inflammatory response in the brain and are associated with senile plaques in Alzheimer's disease (AD). Although there is evidence that microglial activation is important for the pathogenesis of AD , the role of microglia in cerebral amyloidosis remains obscure. The present study was undertaken to investigate the relationship between ␤-amyloid deposition and microglia activation in APP23 transgenic mice which express human mutated amyloid-␤ precursor protein (␤PP) under the control of a neuron-specific promoter element. Light microscopic analysis revealed that the majority of the amyloid plaques in neocortex and hippocampus of 14-to 18-month-old APP23 mice are congophilic and associated with clusters of hypertrophic microglia with intensely stained Mac-1-and phosphotyrosinepositive processes. No association of such activated microglia was observed with diffuse plaques. In young APP23 mice , early amyloid deposits were already of dense core nature and were associated with a strong microglial response. Ultrastructurally , bundles of amyloid fibrils , sometimes surrounded by an incomplete membrane , were observed within the microglial cytoplasm. However , microglia with the typical characteristics of phagocytosis were associated more frequently with dystrophic neurites than with amyloid fibrils. Although the present observations cannot unequivocally determine whether microglia are causal , contributory , or consequential to cerebral amyloidosis , our results suggest that microglia are involved in cerebral amyloidosis either by participating in the processing of neuron-derived ␤PP into amyloid fibrils and/or by ingesting amyloid fibrils via an uncommon phagocytotic mechanism. In any case, our observations demonstrate that neuron-derived ␤PP is sufficient to induce not only amyloid plaque formation but also amyloid-associated microglial activation similar to that reported in AD. Moreover, our results are consistent with the idea that microglia activation may be important for the amyloid-associated neuron loss previously reported in these mice. (Am J Pathol 1999, 154:1673-1684)Substantial evidence supports the view that processing of the amyloid-␤ precursor protein (␤PP) and accumulation of the amyloid-␤ peptide (A␤) in the brain of Alzheimer's disease (AD) patients is crucial to the pathophysiology of the disease. 1,2 Senile amyloid plaques in AD brains are surrounded and infiltrated by activated microglia, which acquire an amoeboid morphology and express various proteins involved in the central nervous system inflammation. [3][4][5] The tight association of amyloid fibrils and microglia has suggested that microglia are somehow involved in either the formation or the phagocytosis of amyloid fibrils. 3,6 -10 Activation of microglia is thought to induce an inflammatory response in the central nervous system and to be a mediator of the amyloid-associated neurodegeneration in AD brain. 11,12 The involvement of inflammation in the progress of AD is underlined by clinical studies showing...

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Section: Activated Microglia Associated With Congophilic Plaques But mentioning

confidence: 85%

Association of Microglia with Amyloid Plaques in Brains of APP23 Transgenic Mice

Stalder¹,

Phinney²,

Probst³

et al. 1999

The American Journal of Pathology

305

201

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“…This suggests that microglia are responding to signals from neurons, some of which are destined to die as a result of seizures. Within 1-4 hours following transient ischemia, microglia are rapidly activated in the CNS (Kato et al, 1994;Nishino et al, 1994;Korematsu et al, 1994). Microglial activation was most intense adjacent to neurons that were destined to die as a result of ischemic insult (Kato et al, 1994).…”

Section: Microgliamentioning

confidence: 99%

Soman-induced seizures rapidly activate astrocytes and microglia in discrete brain regions

1997

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Neurons in the piriform cortex and the pontine nucleus locus coeruleus express elevated levels of the immediate early gene protein product, Fos, within 30-45 minutes of a seizurogenic dose of the anticholinesterase, soman (Zimmer et al., [1997] J. Comp. Neurol. 378:468-481). By 24 hours following soman injection, there is marked neuropathology in the piriform cortex. These findings suggest selective, regional vulnerability in response to the seizurogenic actions of soman. In the present study, we determined that soman-induced seizures also cause selective, rapid activation of astrocytes and microglia in the piriform cortex and other brain regions. Animals were killed at different intervals between 1 hour and 24 hours after a convulsive dose of soman. Brain sections were processed for immunocytochemical detection of astrocytes with antibodies against glial fibrillary acidic protein, and microglia and macrophages with antibodies against the complement receptor 3 protein, OX-42. The results demonstrate that following soman administration: (1) there is a rapid increase in glial fibrillary acidic protein staining in astrocytes of the piriform cortex (1 hour); (ii) reactive astrocytes are specifically restricted to layer II and the superficial boundaries of layer III of the piriform cortex. These are the same layers in which neurons express Fos within 30-45 minutes following soman administration; (3) between 1 and 4 hours, resting (ramified) microglia in the piriform cortex and the hippocampus alter their morphology to resemble active microglia. From 4-8 hours, active microglia undergo morphological changes characteristic of reactive microglia that resemble macrophages. Taken together, these observations indicate that astrocytes and microglia in brain regions susceptible to soman become rapidly "reactive" in response to seizures. The highly specific anatomical codistribution of reactive glia and Fos-expressing neurons suggests that intensely active neurons provide local signals that trigger reactive changes in neighboring glia.

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“…For A␤ antibodies, a 10 min period of 70% formic acid pretreatment was used . Sections stained for phosphotyrosine (P T; Sigma) (Korematsu et al, 1994) or glial fibrillary acidic protein (GFAP; Sigma) were pretreated with a citrate buffer (antigen unveiling system; Vector Laboratories, Burlingame, CA) in a pressure cooker for 1 min after boiling, which facilitated consistent and homogenous labeling throughout the sections. C athepsin B (graciously supplied by Dr. R. A. Nixon, Nathan K line Institute, New York University Medical C enter, Orangeburg, N Y) was diluted at 1:200.…”

Section: Methodsmentioning

confidence: 99%

Protease Inhibitor Coinfusion with Amyloid β-Protein Results in Enhanced Deposition and Toxicity in Rat Brain

Frautschy

Horn²,

Sigel³

et al. 1998

J. Neurosci.

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Amyloid ␤-protein, A␤, is normally produced in brain and is cleared by unknown mechanisms. In Alzheimer's disease (AD), A␤ accumulates in plaque-like deposits and is implicated genetically in neurodegeneration. Here we investigate mechanisms for A␤ degradation and A␤ toxicity in vivo, focusing on the effects of A␤40, which is the peptide that accumulates in apolipoprotein E4-associated AD. Chronic intraventricular infusion of A␤40 into rat brain resulted in limited deposition and toxicity. Coinfusion of A␤40 with the cysteine protease inhibitor leupeptin resulted in increased extracellular and intracellular A␤ immunoreactivity. Analysis of gliosis and TUNEL in neuron layers of the frontal and entorhinal cortex suggested that leupeptin exacerbated A␤40 toxicity. This was supported further by the neuronal staining of cathepsin B in endosomes or lysosomes, colocalizing with intracellular A␤ immunoreactivity in pyknotic cells. Leupeptin plus A␤40 caused limited but significant neuronal phospho-tau immunostaining in the entorhinal cortex. Intriguingly, A␤40 plus leupeptin induced intracellular accumulation of the more toxic A␤, A␤42, in a small group of septal neurons. Leupeptin infusion previously has been reported to interfere with lysosomal proteolysis and to result in the accumulation of lipofuscin, dystrophic neurites, tau-and ubiquitinpositive inclusions, and structures resembling paired helical filaments. Coinfusion of A␤40 with the serine protease inhibitor aprotinin also increased diffuse extracellular deposition but reduced astrocytosis and TUNEL and was not associated with intracellular A␤ staining. Collectively, these data suggest that an age or Alzheimer's-related defect in lysosomal/endosomal function could promote A␤ deposition and DNA fragmentation in neurons and glia similar to that found in Alzheimer's disease.

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Microglial Response to Transient Focal Cerebral Ischemia: An Immunocytochemical Study on the Rat Cerebral Cortex Using Anti-Phosphotyrosine Antibody

Cited by 53 publications

References 27 publications

Association of Microglia with Amyloid Plaques in Brains of APP23 Transgenic Mice

Association of Microglia with Amyloid Plaques in Brains of APP23 Transgenic Mice

Soman-induced seizures rapidly activate astrocytes and microglia in discrete brain regions

Protease Inhibitor Coinfusion with Amyloid β-Protein Results in Enhanced Deposition and Toxicity in Rat Brain

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