Behavioral effects of CD40–CD40L pathway disruption in aged PSAPP mice

Roach, J. Todd; Volmar, Claude‐Henry; Dwivedi, Samvid; Town, Terrence; Crescentini, Robert M.; Crawford, Fiona; Tan, Jun; Mullan, Michael

doi:10.1016/j.brainres.2004.05.004

Cited by 34 publications

(15 citation statements)

References 39 publications

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“…Similar to our studies above, Todd Roach and colleagues [35] showed that PSAPP mice given a regimen of anti-CD40L antibody (commencing at an age when initial Aβ deposition occurs) exhibited superior spatial as well as non-spatial memory compared to non-treatment control animals. Furthermore, Laporte and colleagues [33] demonstrated that APPsw mice deficient for CD40 experience reduced reactive gliosis (microgliosis and astrocytosis) and cerebral Aβ burden compared to CD40-sufficient littermates.…”

Section: The Cd40-cd40l Dyad and Neuroinflammation In Adsupporting

confidence: 83%

“…In support of this CD40-CD40L neuroinflammatory pathway, we and others have demonstrated that microglia are only modestly activated by Aβ exposure in vitro and that co-stimulation with IFN-γ or CD40L synergistically enhances this activation by upregulation of CD40 expression and ligation, respectively [22, 29–35]. Specifically, when cultured microglia are co-administered Aβ peptide and IFN-γ or CD40L in the presence of primary neurons, microglia secrete appreciably high levels of TNF-α, resulting in neuronal injury [28, 36].…”

Section: The Cd40-cd40l Dyad and Neuroinflammation In Admentioning

confidence: 91%

“…Perhaps the most convincing clinical evidence of the role of CD40-CD40L signaling in inflammatory AD-like neurodegeneration comes from clinical studies demonstrating a mild increase of circulating sCD40L in mild cognitive impairment (MCI), which likely represents a prodrome to AD as it is positively associated with increased risk of AD incidence and rapid cognitive decline [35, 38]. This clinical association between sCD40L and AD is also strengthened by evidence of sCD40L engagement of CD40 on endothelial cells resulting in various pro-inflammatory responses, including expression of adhesion molecules and tissue factors, release of cytokines/chemokines and expression of vessel-remodeling metalloproteinases [29,31,38].…”

Section: The Cd40-cd40l Dyad and Neuroinflammation In Admentioning

confidence: 99%

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Impact of the CD40-CD40L Dyad in Alzheimers Disease

Giunta¹,

Rezai‐Zadeh²,

Tan³

2010

CNSNDDT

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As the number of elderly individuals rises, Alzheimer’s disease (AD), marked by amyloid-β deposition, neurofibrillary tangle formation, and low-level neuroinflammation, is expected to lead to an ever-worsening socioeconomic burden. AD pathoetiologic mechanisms are believed to involve chronic microglial activation. This phenomenon is associated with increased expression of membrane-bound CD40 with its cognate ligand, CD40 ligand (CD40L), as well as increased circulating levels of soluble forms of CD40 (sCD40) and CD40L (sCD40L). Here, we review the role of this inflammatory dyad in the pathogenesis of AD. In addition, we examine potential therapeutic strategies such as statins, flavonoids, and human umbilical cord blood transplantation, all of which have been shown to modulate CD40-CD40L interaction in mouse models of AD. Importantly, therapeutic approaches focusing on CD40-CD40L dyad regulation, either alone or in combination with amyloid-β immunotherapy, may provide for a safe and effective AD prophylaxis or treatment in the near future.

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Section: The Cd40-cd40l Dyad and Neuroinflammation In Adsupporting

confidence: 83%

Section: The Cd40-cd40l Dyad and Neuroinflammation In Admentioning

confidence: 91%

Section: The Cd40-cd40l Dyad and Neuroinflammation In Admentioning

confidence: 99%

See 1 more Smart Citation

Impact of the CD40-CD40L Dyad in Alzheimers Disease

Giunta¹,

Rezai‐Zadeh²,

Tan³

2010

CNSNDDT

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“…In addition, CD40 activation increases inflammatory responses and decreases the clearance of Aβ. Disrupting CD40 activation by opposing CD40L activity has shown important in improving spatial memory in animal models of AD [117,118,129,130]. Data from our group and others demonstrate the negative regulation of CD40 activation on microglial cells by CD45 [82].…”

Section: Modulation Of Microglial Activation In Had: Cd40 Cd40l Scdmentioning

confidence: 95%

Flipping the switches: CD40 and CD45 modulation of microglial activation states in HIV associated dementia (HAD)

Salemi

Obregon

Cobb

et al. 2011

Mol Neurodegeneration

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Microglial dysfunction is associated with the pathogenesis and progression of a number of neurodegenerative disorders including HIV associated dementia (HAD). HIV promotion of an M1 antigen presenting cell (APC) - like microglial phenotype, through the promotion of CD40 activity, may impair endogenous mechanisms important for amyloid- beta (Aβ) protein clearance. Further, a chronic pro-inflammatory cycle is established in this manner. CD45 is a protein tyrosine phosphatase receptor which negatively regulates CD40L-CD40-induced microglial M1 activation; an effect leading to the promotion of an M2 phenotype better suited to phagocytose and clear Aβ. Moreover, this CD45 mediated activation state appears to dampen harmful cytokine production. As such, this property of microglial CD45 as a regulatory "off switch" for a CD40-promoted M1, APC-type microglia activation phenotype may represent a critical therapeutic target for the prevention and treatment of neurodegeneration, as well as microglial dysfunction, found in patients with HAD.

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“…These authors undertook a pharmacological approach to elucidate the role of the CD40/CD40L interaction in Ab plaque pathology in an accelerated PSAPP mouse model of AD [78]. In this study, PSAPP mice were treated with a CD40L depleting antibody, and this resulted in marked attenuation of Ab plaque pathology as well as superior spatial memory performance in the Morris water maze task compared with PSAPP mice that received a nonrelevant isotype-matched control antibody [17,79]. …”

Section: Soluble Cd40 and Soluble Cd40 Ligand As Biomarkersmentioning

confidence: 99%

Can peripheral leukocytes be used as Alzheimer’s disease biomarkers?

Rezai‐Zadeh¹,

Gate²,

Szekely³

et al. 2009

Expert Review of Neurotherapeutics

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Alzheimer's disease (AD) is the leading cause of dementia in elderly populations throughout the world and its incidence is on the rise. Current clinical diagnosis of AD requires intensive examination that includes neuropsychological testing and costly brain imaging techniques, and a definitive diagnosis can only be made upon postmortem neuropathological examination. Additionally, antemortem clinical AD diagnosis is typically administered following onset of cognitive and behavioral symptoms. As these symptoms emerge relatively late in disease progression, therapeutic intervention occurs after significant neurodegeneration, thereby limiting efficacy. The identification of noninvasive diagnostic biomarkers of AD is becoming increasingly important to make diagnosis more widely available to clinics with limited access to neuropsychological testing or state-of-the-art brain imaging, reduce the cost of clinical diagnosis, provide a biological measure to track the course of therapeutic intervention, and most importantly, allow for earlier diagnosis -possibly even during the prodromal phase -with hopes of therapeutic intervention prior to appreciable neurodegeneration.

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Behavioral effects of CD40–CD40L pathway disruption in aged PSAPP mice

Cited by 34 publications

References 39 publications

Impact of the CD40-CD40L Dyad in Alzheimers Disease

Impact of the CD40-CD40L Dyad in Alzheimers Disease

Flipping the switches: CD40 and CD45 modulation of microglial activation states in HIV associated dementia (HAD)

Can peripheral leukocytes be used as Alzheimer’s disease biomarkers?

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