The Alzheimer's Aβ-peptide is deposited at sites of complement activation in pathologic deposits associated with aging and age-related macular degeneration

Abstract

Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in older individuals worldwide. The disease is characterized by abnormal extracellular deposits, known as drusen, that accumulate along the basal surface of the retinal pigmented epithelium. Although drusen deposition is common in older individuals, large numbers of drusen and͞or extensive areas of confluent drusen represent a significant risk factor for AMD. Widespread drusen deposition is associated with retinal pigmented epithelial cell dysfunction and degeneration of the photoreceptor cells of the neural retina. Recent studies have shown that drusen contain a variety of immunomodulatory molecules, suggesting that the process of drusen formation involves local inflammatory events, including activation of the complement cascade. Similar observations in Alzheimer's disease (AD) have lead to the hypothesis that chronic localized inflammation is an important element of AD pathogenesis, with significant neurodegenerative consequences. Accordingly, the amyloid beta (A␤) peptide, a major constituent of neuritic plaques in AD, has been implicated as a primary activator of complement in AD. Here we show that A␤ is associated with a substructural vesicular component within drusen. A␤ colocalizes with activated complement components in these ''amyloid vesicles,'' thereby identifying them as potential primary sites of complement activation. Thus, A␤ deposition could be an important component of the local inflammatory events that contribute to atrophy of the retinal pigmented epithelium, drusen biogenesis, and the pathogenesis of AMD. C urrent theories of Alzheimer's disease (AD) pathogenesis include inflammatory processes as significant contributors to the disease process (1). Chronic local inflammation, including both direct and bystander cell damage attributable to complement-mediated attack, exacerbates the effects of primary AD pathogenic stimuli. Amyloid beta (A␤) has been implicated in activation of the complement cascade (2) and is a major component of AD plaques, where it colocalizes with activated complement components, the C5b-9 membrane attack complex (MAC), acute phase reactants, and other inflammatory mediators (3-5).New evidence suggests that a strikingly similar, chronic local inflammatory component is also associated with the formation of drusen, the age-related extracellular deposits that are often linked with age-related macular degeneration (AMD) (6-9). AMD is a retinal degenerative disease that leads to loss of central vision, and affects 5-10% of the population over 60 years of age. Drusen form between the basal surface of an epithelial monolayer derived from neuroectoderm that is known as the retinal pigmented epithelium (RPE), and a basement membrane complex called Bruch's membrane (Fig. 1). Small numbers of drusen are present in the eyes of many older individuals; however, numerous and͞or confluent drusen are associated clinically with geographic atrophy of the RPE (10) and with a significantly increased risk of ...

The expression of advanced glycation endproduct receptors in rpe cells associated with basal deposits in human maculas

“…The location and composition of these deposits distinguish aging from AMD. Basal laminar deposits (BlamD), which form between the RPE cell and basement membrane, are a normal aging change early, but become specific for AMD when they become thick and contain cellular debris, 'long spaced collagen', membranous structures, lipid, and inflammatory proteins (Sarks, 1976;Newsome et al, 1987;Green and Enger, 1993;van der Schaft et al, 1994;Spraul et al, 1996;Spraul and Grossniklaus, 1997;Curcio and Millican, 1999;Anderson and Ozaki, 2001;Johnson et al, 2002;Leu et al, 2002). The most sensitive and specific histopathologic marker of AMD is basal linear deposits (BlinD), which form in the inner collagenous layer of Bruch's membrane.…”

“…The composition and location of these deposits distinguishes chronological aging from age-related disease. Basal laminar deposits, which develop between the RPE cell and basement membrane, are specific for age-related macular degeneration (AMD) when they are thick and contain heterogeneous debris such as long spaced collagen (Sarks, 1976;Newsome et al, 1987;Green and Enger, 1993;van der Schaft et al, 1994;Spraul et al, 1996;Spraul and Grossniklaus, 1997;Curcio and Millican, 1999;Anderson et al, 2001;Johnson et al, 2002;Leu et al, 2002). Basal linear deposits occur within the inner collagenous layer, and are the most specific basal deposit for AMD (Sarks, 1976;Newsome et al, 1987;Green and Enger, 1993;van der Schaft et al, 1994;Spraul et al, 1996;Spraul and Grossniklaus, 1997;Curcio and Millican, 1999;Anderson et al, 2001;Johnson et al, 2002;Leu et al, 2002).…”

Classical complement activation and acquired immune response pathways are not essential for retinal degeneration in the rd1 mouse

“…Local inflammation may not only be involved in the formation of drusen, a hallmark of AMD (Hageman et al 2001;Johnson et al 2002) but inflammation triggered by the debris generated by dying RPE cells may also lead to photoreceptor cell death and loss of vision (Johnson et al 2002). Furthermore, mutations in complement factor H and factor B were shown to significantly increase the risk to develop age-related macular degeneration (AMD) (Edwards et al 2005;Hageman et al 2005;Haines et al 2005;Klein et al 2005;Umeda et al 2005;Gold et al 2006).…”

Unfolding the therapeutic potential of chemical chaperones for age-related macular degeneration

“…In Alzheimer's, these plaques are composed of aggregated beta-amyloid; and in Parkinson's, alpha-synuclein protein bound to ubiquitin accumulates in cytoplasmic inclusions known as Lewy bodies because the alpha-synuclein-ubiquitin complex cannot be directed to the proteasome [13,51]. Drusen, commonly associated with AMD progression, is an extracellular deposit in Bruch's membrane between the RPE and choroid that consists of glycoprotein, lipid, complement components, and amyloid.…”

“…Interestingly, drusen contains several protein components found in other amyloid diseases, including vitronectin, amyloid P, apolipoprotein E (ApoE), amyloid-beta oligomers, and oxidatively modified proteins. These component similarities between drusen and the extracellular deposits of protein folding disorders suggest that the lesions in AMD may also be due to protein misfolding and/or aggregation [51,52]. In fact, the amyloid beta oligomers in drusen were characterized as nonfibrillar oligomers (i.e.…”