Peripheral T cells overexpress MIP-1α to enhance its transendothelial migration in Alzheimer's disease

Man, Shumei; Ma, Yanhong; Shang, De-Shu; Zhao, Wei‐Dong; Li, Bo; Guo, Dawen; Fang, Wen-Gang; Zhu, Li; Chen, Yuhua

doi:10.1016/j.neurobiolaging.2006.02.013

Cited by 116 publications

(105 citation statements)

References 47 publications

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“…We previously found that CCR5 expression in HBMECs was upregulated by A␤ in a time-and dose-dependent manner (28), but the mechanism is not known. To determine the signal pathway of A␤-dependent CCR5 expression, we first examined the effect of pharmacological inhibitors of MAPK and PI3K on CCR5 expression.…”

Section: Erk Jnk and Pi3k Activation Is Related To A␤-up-regulated mentioning

confidence: 98%

“…6, B and C). Our previous studies showed that MIP-1␣, a CCR5 ligand, is overexpressed in AD patients' T cells contributed to T cell TEM (28). It is known that CCR5 and CCL5, another CCR5 ligand, are expressed on T cells (50).…”

Section: A␤-activated Signal Pathway From Rage To Egr-1 Is Required Fmentioning

confidence: 99%

“…The HBMEC monolayer cultured on Transwell insert has been broadly used as an in vitro BBB model (28,48,49). Based on the BBB model, we previously showed that A␤-induced CCR5 expression was related to T cells crossing the HBMEC monolayer (28).…”

Section: A␤-activated Signal Pathway From Rage To Egr-1 Is Required Fmentioning

confidence: 99%

“…Based on the BBB model, we previously showed that A␤-induced CCR5 expression was related to T cells crossing the HBMEC monolayer (28). In this study, to mimic AD brain's microenvironment, the A␤-containing in vitro BBB model was constructed.…”

Section: A␤-activated Signal Pathway From Rage To Egr-1 Is Required Fmentioning

confidence: 99%

“…induce tight junction opening for T cell TEM, and that CCR5 expression in human brain microvascular endothelial cells (HBMECs) was up-regulated by A␤ in a time-and dose-dependent manner (28). The aim of this study is to explore the mechanism of CCR5 up-regulation by A␤.…”

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confidence: 99%

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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

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103

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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: Erk Jnk and Pi3k Activation Is Related To A␤-up-regulated mentioning

confidence: 98%

Section: A␤-activated Signal Pathway From Rage To Egr-1 Is Required Fmentioning

confidence: 99%

Section: A␤-activated Signal Pathway From Rage To Egr-1 Is Required Fmentioning

confidence: 99%

Section: A␤-activated Signal Pathway From Rage To Egr-1 Is Required Fmentioning

confidence: 99%

mentioning

confidence: 99%

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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

Self Cite

103

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Human‐BasedIn VitroBrain Endothelial Cell Models

Wilson

Shusta

2015

Blood‐Brain Barrier in Drug Discovery

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The Role of Immunity in Alzheimer's Disease

McManus

2022

Advanced Biology

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Based on this, it has been suggested that reducing co-morbidities in the elderly and extending the period of healthy aging will have a significant impact on decreasing the number of individuals with such impairments in 2050, with a knock-on effect of reducing the cost of dementia care.It is widely acknowledged that neuroinflammation is a critical step on the road to dementia. It is produced as a reaction to the ongoing protein deposition and cell loss observed in individuals with cognitive impairment and it has been argued that such inflammatory factors can in turn exacerbate ongoing cellular changes and hasten the progression to severe cognitive decline. This review will detail the role of the innate and adaptive immune system in the progression of AD. Specifically we will cover microglia mediated-neuroinflammation and the contribution of peripheral cells, namely T cells, on the progression to cognitive decline and the potential therapies that are under development to tackle these pathways will be discussed. Alzheimer's DiseaseThe most common cause of cognitive impairment or dementia is AD. This accounts for 60-80% of dementia cases [5] and is characterized by the build-up of two different proteins, amyloid-β (Aβ) and tau, along with cognitive changes. Aβ is cleaved from amyloid precursor protein (APP) and these monomers aggregate into oligomers and fibrils, ultimately forming Aβ-containing plaques that are 200-650 μm 2 in size. [6] Aβ can also undergo posttranslational modifications such as phosphorylation and nitration, which accelerate this process. [7,8] Tau is a protein found in neurons that is involved in microtubule stabilization, however in AD (and other Frontotemporal dementias -FTDs) tau becomes hyperphosphorylated and accumulates forming neurofibrillary tangles (NFTs). These deposits vary considerably in size from 10 to 500 μm 2 . [9] The severity of pathological changes (particularly the NFTs) correlate with neuronal loss and the increasing cognitive decline in those with AD. [10][11][12] The observed cognitive impairment in AD differs significantly across disease stages, and ranges from mild cognitive impairment (MCI), which can progress to moderate and then severe dementia. Indeed 68-80% of those who receive an initial diagnosis of MCI go on to develop AD within 6 years. [13][14][15] MCI is the first stage of cognitive decline and features initial With the increase in the aging population, age-related conditions such as dementia and Alzheimer's disease will become ever more prevalent in society. As there is no cure for dementia and extremely limited therapeutic options, researchers are examining the mechanisms that contribute to the progression of cognitive decline in hopes of developing better therapies and even an effective, long-lasting treatment for this devastating condition. This review will provide an updated perspective on the role of immunity in triggering the changes that lead to the development of dementia. It will detail the latest findings on Aβ-and tau-induced microglial activation, i...

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Peripheral T cells overexpress MIP-1α to enhance its transendothelial migration in Alzheimer's disease

Cited by 116 publications

References 47 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

Human‐BasedIn VitroBrain Endothelial Cell Models

The Role of Immunity in Alzheimer's Disease

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