Chemokine receptor 5 antagonist d-Ala-peptide T-amide reduces microglia and astrocyte activation within the hippocampus in a neuroinflammatory rat model of Alzheimer's disease

Rosi, Susanna; Pert, Candace B.; Ruff, Michael R.; McGann-Gramling, Kristin; Wenk, Gary L.

doi:10.1016/j.neuroscience.2005.04.029

Cited by 58 publications

(37 citation statements)

References 21 publications

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“…CCR5, particularly RAGE, has been implicated in the pathogenesis of AD. Evidence showed that the chemokine receptor CCR5 is up-regulated in AD brain and plays a role in the recruitment and accumulation of microglia in senile plaques (55,74). The major features of RAGE activation in contributing to AD result from its interaction with A␤.…”

Section: Discussionmentioning

confidence: 99%

Amyloid β Interaction with Receptor for Advanced Glycation End Products Up-Regulates Brain Endothelial CCR5 Expression and Promotes T Cells Crossing the Blood-Brain Barrier

Shang²,

Zhao³

et al. 2009

The Journal of Immunology

104

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How circulating T cells infiltrate into the brain in Alzheimer disease (AD) remains unclear. We previously reported that amyloid β (Aβ)-dependent CCR5 expression in brain endothelial cells is involved in T cell transendothelial migration. In this study, we explored the signaling pathway of CCR5 up-regulation by Aβ. We showed that inhibitors of JNK, ERK, and PI3K significantly decreased Aβ-induced CCR5 expression in human brain microvascular endothelial cells (HBMECs). Chromatin immunoprecipitation assay revealed that Aβ-activated JNK, ERK, and PI3K promoted brain endothelial CCR5 expression via transcription factor Egr-1. Furthermore, neutralization Ab of receptor for advanced glycation end products (RAGE; an Aβ receptor) effectively blocked Aβ-induced JNK, ERK, and PI3K activation, contributing to CCR5 expression in HBMECs. Aβ fails to induce CCR5 expression when truncated RAGE was overexpressed in HBMECs. Transendothelial migration assay showed that the migration of MIP-1α (a CCR5 ligand)-expressing AD patients’ T cells through in vitro blood-brain barrier model was effectively blocked by anti-RAGE Ab, overexpression of truncated RAGE, and dominant-negative PI3K, JNK/ERK, or Egr-1 RNA interference in HBMECs, respectively. Importantly, blockage of intracerebral RAGE abolished the up-regulation of CCR5 on brain endothelial cells and the increased T cell infiltration in the brain induced by Aβ injection in rat hippocampus. Our results suggest that intracerebral Aβ interaction with RAGE at BBB up-regulates endothelial CCR5 expression and causes circulating T cell infiltration in the brain in AD. This study may provide a new insight into the understanding of inflammation in the progress of AD.

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Section: Discussionmentioning

confidence: 99%

Amyloid β Interaction with Receptor for Advanced Glycation End Products Up-Regulates Brain Endothelial CCR5 Expression and Promotes T Cells Crossing the Blood-Brain Barrier

Shang²,

Zhao³

et al. 2009

The Journal of Immunology

104

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“…What was interesting in our data set of 44K genes is that these same receptors were identified as some of the most highly upregulated genes in AD when compared to other forms of dementia. In certain reports, chemokine receptors are expressed by activated microglia and some, such as CCR5, may actually play a role in microglia recruitment to senile plaques [22], possibly due to the presence of increased levels of amyloid beta. It has been suggested that chemokine receptor antagonists may be of great import in reducing the level of neuroinflammation associated with Alzheimer's disease and may even slow its onset [22].…”

Section: Discussionmentioning

confidence: 99%

“…In certain reports, chemokine receptors are expressed by activated microglia and some, such as CCR5, may actually play a role in microglia recruitment to senile plaques [22], possibly due to the presence of increased levels of amyloid beta. It has been suggested that chemokine receptor antagonists may be of great import in reducing the level of neuroinflammation associated with Alzheimer's disease and may even slow its onset [22]. In the current report, we demonstrate, for the first time, that CXCR4 is highly expressed in the IPLs and by glial cells in AD subjects when compared to age-matched controls.…”

Section: Discussionmentioning

confidence: 99%

Alterations in immunological and neurological gene expression patterns in Alzheimer's disease tissues

Weeraratna

Kalehua

DeLeon

et al. 2007

Experimental Cell Research

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Microarray technology was utilized to isolate disease-specific changes in gene expression by sampling across inferior parietal lobes of patients suffering from late onset AD or non-AD-associated dementia and non-demented controls. Primary focus was placed on understanding how inflammation plays a role in AD pathogenesis. Gene ontology analysis revealed that the most differentially expressed genes related to nervous system development and function and neurological disease followed by genes involved in inflammation and immunological signaling. Pathway analysis also implicated a role for chemokines and their receptors, specifically CXCR4 and CCR3, in AD. Immunohistological analysis revealed that these chemokine receptors are upregulated in AD patients. Western analysis demonstrated an increased activation of PKC, a downstream mediator of chemokine receptor signaling, in the majority of AD patients. A very specific cohort of genes related to amyloid beta accumulation and clearance were found to be significantly altered in AD. The most significantly downregulated gene in this data set was the endothelin converting enzyme 2 (ECE2), implicated in amyloid beta clearance. These data were subsequently confirmed by real-time PCR and Western blot analysis. Together, these findings open up new avenues of investigation and possible therapeutic strategies targeting inflammation and amyloid clearance in AD patients.

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“…Consequently, microglia become activated either by a direct interaction with misfolded Aβ molecules via pattern recognition receptors (PRR), or by complement activation in the response to Aβ depositions which leads to the formation of the pro-inflammatory molecule C5a [14]. Enhanced microglia activation then leads to excessive release of proinflammatory cytokines [20], chemokines [21,22], and further complement components [23,24], as well as the release of reactive oxygen and nitrogen species [25,26]. These pro-inflammatory mediators cause a number of stress conditions which, in turn, are supposed to reinforce Aβ production and aggregation [28,30,31,42,43].…”

Section: Discussionmentioning

confidence: 99%

“…Aβ aggregates cause direct cytotoxicity and self-propagation, but also a constant, selfsustaining inflammatory environment by prolonged activation of astroglial [17,18] and microglial cells [19]. Activation of microglia by Aβ and complement is supposed to promote the excessive release of proinflammatory cytokines [20], chemokines [21,22], and further complement components [23,24], as well as the release of reactive oxygen and nitrogen species [25,26], altogether leading to dysfunction and loss of synapse signaling [27]. Pro-inflammatory mediators provoke a number of stress conditions which, in turn, can enhance APP production and processing to amyloid peptides (Aβ 1-42) [28][29][30][31].…”

Section: Introductionmentioning

confidence: 99%

Combinatorial Vaccine against Complement Factor C5a and Amyloid Beta: A New Therapeutic Approach in Alzheimers Disease

linger¹,

Mihailovska²,

M³

et al. 2017

J Clin Cell Immunol

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Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by neuronal loss due to amyloid beta (Aβ) aggregations, neurofibrillary tangles, and prominent neuroinflammation. Inflammatory processes in AD primarily occur in response to misfolded and aggregated proteins, or mislocalized nucleic acids and reactive microglia. Prolonged chronic neuroinflammation is thought to reinforce neuronal cell dysfunction and cell death. In our previous study we demonstrated that the interference with the pro-inflammatory mediator C5a by AFF1 vaccine at an early stage of disease is able to reduce microglia activation and amyloid plaque burden which is accompanied by ameliorated memory deficiency in Tg2576 mice, a mouse model of AD. In a follow-up study we tested the effect of a combinatorial vaccine targeting neuroinflammation by C5a and Aβ aggregates, two detrimental processes in AD. The amyloid plaque burden in the brain of Tg2576 mice was significantly reduced upon vaccination by the monovalent anti-C5a (AFF1) as well as anti-Aβ (AD02) vaccine, however, the combinatorial AFF1/AD02 vaccine showed a clear additive beneficial effect. Moreover, contextual memory in Tg2576 mice was significantly improved by the combinatorial AFF1/AD02 vaccine when compared to monovalent or control vaccines. Thus, targeting two neuropathological processes such as neuroinflammation and Aβ aggregation may represent a new and promising approach for the treatment of AD.

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Chemokine receptor 5 antagonist d-Ala-peptide T-amide reduces microglia and astrocyte activation within the hippocampus in a neuroinflammatory rat model of Alzheimer's disease

Cited by 58 publications

References 21 publications

Amyloid β Interaction with Receptor for Advanced Glycation End Products Up-Regulates Brain Endothelial CCR5 Expression and Promotes T Cells Crossing the Blood-Brain Barrier

Amyloid β Interaction with Receptor for Advanced Glycation End Products Up-Regulates Brain Endothelial CCR5 Expression and Promotes T Cells Crossing the Blood-Brain Barrier

Alterations in immunological and neurological gene expression patterns in Alzheimer's disease tissues

Combinatorial Vaccine against Complement Factor C5a and Amyloid Beta: A New Therapeutic Approach in Alzheimers Disease

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