Enhanced soluble CD40 ligand and Alzheimer's disease: Evidence of a possible pathogenetic role
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.
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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.
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These authors contributed equally to this work.