Elsevier

Neurobiology of Aging

Volume 29, Issue 3, March 2008, Pages 348-356
Neurobiology of Aging

Enhanced soluble CD40 ligand and Alzheimer's disease: Evidence of a possible pathogenetic role

https://doi.org/10.1016/j.neurobiolaging.2006.10.019Get rights and content

Abstract

It has been suggested that cerebrovascular factors contribute to Alzheimer's disease. Soluble CD40 ligand (sCD40L) is directly involved in the development of vascular damage. We tested the hypothesis that sCD40L may be enhanced in Alzheimer's disease and predictive of its clinical course.

Plasma sCD40L levels were evaluated in three groups of 40 consecutive patients each referring for mild or moderate or severe Alzheimer's disease, as assessed by the Clinical Dementia Rating (CDR), and in 40 healthy subjects. Seventy-seven patients with mild or moderate disease were re-evaluated after 2 years. Cross-sectional comparisons revealed higher plasma sCD40L levels in Alzheimer's disease patients than in controls (9.3 ± 4.7 ng/mL versus 3.4 ± 1.3 ng/mL, p < 0.0001). Circulating sCD40L levels significantly increased through the three CDR stages (p = 0.0011 or less) and were correlated with MMSE (r = −0.574, p < 0.0001) and ADAS-cog subscale (r = 0.538, p < 0.0001) scores. Longitudinal evaluation identified sCD40L as an independent predictor of MMSE (β = −0.157, t = −3.650, p = 0.0005) and ADAS-cog subscale (β = 0.484, t = 3.890, p = 0.0002) score changes after 2 years. Patients with plasma sCD40L level  6.0 ng/mL, identified by ROC curve analysis as the best discriminating value for disease progression, had a three-fold increase in the risk of progression toward a worse CDR stage (odd ratio: 3.0, C.I. 95% 1.2–8.1).

In conclusion, circulating sCD40L is enhanced in patients with Alzheimer's disease and independently associated with the severity and progression of the disease. These data might suggest a pathogenetic role for sCD40L in Alzheimer's disease.

Introduction

Alzheimer's disease (AD) is the most common dementing illness, affecting at least 15 million persons throughout the world (Khachaturian, 1997, Reisberg et al., 1997). Although the neuropathological hallmarks of neurofibrillary tangles and senile plaques have been described a century ago, there is disagreement about the basic nature of the disease.

Neurodegeneration, a process of neuronal dysfunction and death independent on vascular factors, has long been considered the main pathogenetic process underlying AD (Cummings and Cole, 2002). Recent clinical studies have begun to challenge the assumption that AD is the result of a pure neurodegenerative process independent of vascular insufficiency. Indeed, factors that predispose to cerebrovascular disease also increase the risk for AD (Breteler, 2000). Furthermore, the presence of ischemic brain lesions worsens the cognitive deficit in AD (Snowdon et al., 1997). Finally, alterations in cerebral blood flow and cerebrovascular regulation precede the onset of AD (Johnson and Albert, 2000). These data indicate that vascular-related factors might play a part in the pathophysiology of AD by reducing cerebral perfusion to a critical level of dysfunction (de la Torre, 2000).

In this regard, it is now generally accepted that CD40–CD40 ligand (CD40L) interaction is critically involved in multiple ways in the pathophysiology of risk factor-related vascular damage (Andre et al., 2002). Originally identified in B and T lymphocytes as being involved in T cell-dependent B cell activation and differentiation, the CD40–CD40L system has been implicated in the pathophysiology of several chronic inflammatory diseases including risk factor-related vascular damage. CD40, a 50-kDa integral membrane protein of the tumor necrosis factor receptor family, and its cognate ligand CD40L, also known as CD154, a transmembrane 39-kDa protein structurally related to tumor necrosis factor-α, are coexpressed by several cells of the vasculature, including endothelial cells, smooth muscle cells and macrophages (Mach et al., 1997). CD40L also occurs in a soluble form that is considered to possess a full biological activity (Graf et al., 1995). Increased soluble CD40L levels have been described in obesity (Desideri and Ferri, 2003), hypercholesterolemia (Cipollone et al., 2002), diabetes (Cipollone et al., 2005, Santilli et al., 2006) and unstable angina (Aukrust et al., 1999). Furthermore, it has been recently reported that circulating soluble CD40L has a strong independent prognostic value among apparently healthy individuals (Schonbeck et al., 2001) and patients with acute coronary syndromes (Heeschen et al., 2003) and represents an independent predictor of restenosis after percutaneous transluminal angioplasty (Cipollone et al., 2003). Thus, the clinical association between soluble CD40L and cardiovascular events suggests that soluble CD40L function spans the time interval from early atherogenesis to late thrombotic complications.

Studies on the cellular distribution of CD40 ligand indicate that >95% of the circulating soluble CD40L exists in platelets (Andre et al., 2002). CD40 ligand is rapidly translocated to the platelet surface after stimulation and then it is cleaved from the platelets over a period of minutes to hours, subsequently generating a soluble fragment (Andre et al., 2002). This suggests that platelet stimulatory events must be considered in the biological and pathological context of soluble CD40L function. Worth mentioning, in this context, is the demonstration of multiple abnormalities in platelet structure and/or function in patients with AD (Sevush et al., 1998). Starting from these evidences, it is tempting to hypothesize that enhanced soluble CD40L signaling may occur in patients with AD and affect the clinical course of the disease.

To verify this hypothesis, we performed a cross-sectional comparison of circulating levels of soluble CD40L between patients with either mild or moderate or severe AD and cognitively normal subjects. Moreover, we performed a longitudinal study to evaluate the predictive value of soluble CD40L with respect to clinical progression of AD.

Section snippets

Study participants

The study population comprised 120 Caucasian subjects with probable AD as diagnosed on the basis of the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria (McKhann et al., 1984). Between May 2002 and October 2003, patients were recruited consecutively among those referring to the Outpatient Units of the Geriatric Divisions of the Universities of L’Aquila and Ferrara. The patients were

Baseline clinical characteristics

The baseline characteristics of study populations are summarized in Table 1. No significant differences were found between the three CDR stages and controls with respect to the general characteristics (Table 1). As expected, MMSE score significantly decreased while ADAS-cog score significantly increased through the three CDR stages (Table 1). In addition, illness duration increased through the three CDR stages (Table 1).

Cross-sectional evaluation of circulating soluble CD40L levels in patients with Alzheimer's disease and in cognitively normal subjects

Plasma levels of soluble CD40L were significantly higher in patients with

Discussion

From the earliest history of AD, cerebrovascular mechanisms have been suspected of playing a role in the pathogenesis of the disease. Although scientific research has since directed greater attention to molecular mechanisms centered on neurodegeneration, a large and diverse body of evidence from studies in humans and in experimental models has pointed consistently to a link between Alzheimer's and vascular factors. Our study sheds new light on this topic by demonstrating for the first time (a)

Disclosure statement

All authors disclose any actual or potential conflicts of interest including any financial, personal or other relationships with other people or organizations within 3 years of beginning the work that could inappropriately influence it. The study was conducted according to the principles of the Helsinki Declaration.

Acknowledgment

This work was supported in part by a grant from the Italian Society of Hypertension.

References (43)

  • P. Andre et al.

    Platelet-derived CD40L: the switch-hitting player of cardiovascular disease

    Circulation

    (2002)
  • P. Aukrust et al.

    Enhanced levels of soluble and membrane-bound CD40 ligand in patients with unstable angina

    Circulation

    (1999)
  • P.A. Boyle et al.

    Mild cognitive impairment: risk of Alzheimer disease and rate of cognitive decline

    Neurology

    (2006)
  • Ciabattoni, G., Porreca, E., Di Febbo, C., Di Iorio, A., Paganelli, R., Bucciarelli, T., Pescara, L., Del Re, L.,...
  • F. Cipollone et al.

    Enhanced soluble CD40 ligand contributes to endothelial cell dysfunction in vitro and monocyte activation in patients with diabetes mellitus: effect of improved metabolic control

    Diabetologia

    (2005)
  • F. Cipollone et al.

    Preprocedural level of soluble CD40L is predictive of enhanced inflammatory response and restenosis after coronary angioplasty

    Circulation

    (2003)
  • F. Cipollone et al.

    Association between enhanced soluble CD40L and prothrombotic state in hypercholesterolemia: effects of statin therapy

    Circulation

    (2002)
  • J.L. Cummings et al.

    Alzheimer disease

    JAMA

    (2002)
  • G. Desideri et al.

    Effects of obesity and weight loss on soluble CD40L levels

    JAMA

    (2003)
  • K. Fassbender et al.

    Simvastatin strongly reduces levels of Alzheimer's disease beta-amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo

    Proc. Natl. Acad. Sci. U.S.A.

    (2001)
  • D. Graf et al.

    A soluble form of TRAP (CD40 ligand) is rapidly released after T cell activation

    Eur. J. Immunol.

    (1995)
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    These authors contributed equally to this work.

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