Archive for the 'cd40' Category

Diagnostic utility of APOE, soluble CD40, CD40L, and Abeta1-40 levels in plasma in Alzheimer's disease

By Ait-ghezala G, Abdullah L, Volmar CH, Paris D, Luis CA, Quadros A, Mouzon B, Mullan MA, Keegan AP, Parrish J, Crawford FC, Mathura VS, Mullan MJ.

Cytokine. 2008 Nov;44(2):283-7.

A continuous inflammatory state is associated with Alzheimer’s disease (AD) evidenced by an increase in proinflammatory cytokines around beta-amyloid (Abeta) deposits. In addition, functional loss of CD40L is shown to result in diminished Amyloid precursor proton (APP) processing and microglial activation, supporting a prominent role of CD40-CD40L in AD etiology. We therefore hypothesize that a peripheral increase in Abeta may result in corresponding increase of sCD40 and sCD40L further contributing to AD pathogenesis. We measured plasma Abeta, sCD40 and sCD40L levels in 73 AD patients and compared to 102 controls matched on general demographics. We demonstrated that Abeta(1-40), levels of sCD40 and sCD40L are increased in AD and declining MMSE scores correlated with increasing sCD40L, which in turn, correlated positively with Abeta(1-42). We then combined sCD40, sCD40L, Abeta and APOE and found that this biomarker panel has high sensitivity and specificity (>90%) as a predictor of clinical AD diagnosis. Given the imminent availability of potentially disease modifying therapies for AD, a great need exists for peripheral diagnostic markers of AD. Thus, we present preliminary evidence for potential usefulness for combination of plasma sCD40, sCD40L along with Abeta(1-40) and APOE epsilon4 in improving the clinical diagnosis of AD.

The Roskamp Institute is devoted to understanding causes and finding cures for neuropsychiatric and neurodegenerative disorders and addictions. The Institute utilizes a broad range of scientific approaches to understanding the causes of and potential therapies for these disorders with an emphasis on Alzheimer’s disease. For more information, please call (941)752-2949

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CD40/CD40L interaction induces Abeta production and increases gamma-secretase activity independently of tumor necrosis factor receptor associated factor (TRAF) signaling.

By Volmar CH, Ait-Ghezala G, Frieling J, Weeks OI, Mullan MJ.

Exp Cell Res. 2009 Aug 1;315(13):2265-74.

CD40, a member of tumor necrosis factor receptor superfamily, and its cognate ligand CD40L are both elevated in the brain of Alzheimer’s disease (AD) patients compared to controls. We have shown that pharmacological or genetic interruption of CD40/CD40L interaction results in mitigation of AD-like pathology in vivo in transgenic AD mouse models, and in vitro. Recently, we showed that CD40L stimulation could increase Abeta levels via NFkappaB signaling, presumably through TRAFs. In the present work, using CD40 mutants, we show that CD40L can increase levels of Abeta(1-40), Abeta(1-42), sAPPbeta, sAPPalpha and CTFbeta independently of TRAF signaling. We report an increase in mature/immature APP ratio after CD40L treatment of CD40wt and CD40-mutant cells, reflecting alterations in APP trafficking. In addition, results from CD40L treatment of a neuroblastoma cell line over-expressing the C-99 APP fragment suggest that CD40L has an effect on gamma-secretase. Furthermore, inhibition of gamma-secretase activity significantly reduces sAPPbeta levels in the CD40L treated HEK/APPsw CD40wt and the CD40-mutant cells. The latter suggests CD40/CD40L interaction primarily acts on gamma-secretase and affects beta-secretase via a positive feedback mechanism. Taken together, our data suggest that CD40/CD40L interaction modulates APP processing independently of TRAF signaling.

The Roskamp Institute is devoted to understanding causes and finding cures for neuropsychiatric and neurodegenerative disorders and addictions. The Institute utilizes a broad range of scientific approaches to understanding the causes of and potential therapies for these disorders with an emphasis on Alzheimer’s disease. For more information, please call (941)752-2949

CD40L induces Abeta production via signaling by the granulocyte macrophage colony stimulating factor (GM-CSF)

Alzheimer’s disease (AD) is the most common type of dementia in the elderly. AD is mainly characterized by the accumulation of a small molecule (known as amyloid beta (Abeta)) in the brain. Many researchers have shown that the molecule CD40L is elevated in AD patients. Roskamp Institute research group headed by Dr. Michael Mullan also have recently shown that CD40L stimulation increases Abeta levels in cellular models of the disease. Furthermore, we have shown that CD40L stimulation of cells that are important for the defense of the nervous system induces increases in pro-inflammatory molecules known as cytokines. The granulocyte macrophage colony stimulating factor (GM-CSF) is one of these cytokines involved in inflammation responses in the brain. Numerous studies have correlated AD with increases in pro-inflammatory cytokines. In the cytokine paper, we have shown that CD40L stimulation increases the levels of both GM-CSF and Abetain AD cell models. We have shown that treatment of these cells with GM-CSF causes a time dependent significant increase in Abeta levels. We demonstrate that blocking GM-CSF reduces CD40L-induced Abeta production in a dose dependent manner. In addition, we show that inhibiting GM-CSF signaling by silencing the GM-CSF receptor gene significantly reduces Abeta levels to below basal levels in non-CD40L-stimulated by blocking the trafficking of Abeta’s mother protein, the amyloid precursor protein. Our results that are now published in the Journal cytokine (Volmar et al., in press) suggest that GM-CSF operates downstream of CD40/CD40L interaction and that GM-CSF modulates Abeta production.