Elsevier

Experimental Neurology

Volume 184, Issue 2, December 2003, Pages 697-704
Experimental Neurology

Immunohistochemical study of distribution of apolipoproteins E and D in human cerebral β amyloid deposits

https://doi.org/10.1016/S0014-4886(03)00315-7Get rights and content

Abstract

Several molecules are known to be closely associated with amyloid deposits in human brain. Among these, apolipoproteins such as apolipoproteins E (apo E) and J (apo J) have been found in two neuropathological hallmarks of Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA): senile plaques (SPs) and cerebrovascular amyloid. These apolipoproteins may be implicated in amyloid fibrillogenesis. Apo D is a multiligand–multifunctional glycoprotein present in SPs, as we previously reported. The aim of this work is to study the link between immunolocalization of apo E and apo D in AD and CAA brains. Both apolipoproteins were found in all types of SPs, but apo E was observed more often than apo D in mature plaques. Whereas apo E is always located overlapping the amyloid core, apo D seems to situate preferably around and near the amyloid. Immunohistochemistry revealed that these apolipoproteins behave differently in cerebral vessels. Apo E labeling in vessels appears mainly linked to amyloid deposits, whereas apo D shows a distribution almost opposite to that of apo E. This could be an indication of the different roles that each apolipoprotein plays in the pathogenesis of amyloid deposition.

Introduction

Amyloid β-peptide (A β) deposition is a prominent feature of a great number of brain disorders, including cerebral amyloid angiopathy (CAA), Alzheimer's disease (AD), Down's syndrome (DS), and hereditary cerebral hemorrhage with amyloidosis of Ducht type (HCHWA-D). It also appears in normal aging Ghiso and Frangione, 2001, Jellinger, 2002.

A β fibrils are found in the walls of cortical and leptomeningeal vessels, in the extracellular medium (senile plaques, SPs), and within neurons (neurofibrillary tangles, NFTs). A β is a 39- to 44-residue-long peptide arising from a large amyloid precursor protein (APP) by an incompletely understood series of proteolytic steps that involve a change in the processing of APP by α-secretase (Xia, 2001). The result is that some A β forms (A β40 and A β42) contribute differently to the formation of insoluble filaments in amyloid deposits. CAA lesions consist mainly of A β40, and SPs mainly of A β42 (Yamada, 2000). The differing compositions of A β in CAA and SPs may be produced by distinct and probably independent mechanisms. It is likely that neurons are the major candidates for production of APP and A β in SPs, whereas smooth muscle cells and pericytes produce A β in CAA (Verbeek et al., 1998).

Apolipoprotein E (apo E) has been described both immunohistochemically and biochemically as a constituent of A β deposits, along with many other amyloid-associated proteins. The presence of apo E in SPs and its ability to form, at least in vitro, amyloid-like fibrils from A β raise speculation that apo E could alter their conformation to favor fibril growth Vickers et al., 2000, Wisniewski et al., 1994. However, apo E is not the only apolipoprotein that plays a role in amyloidosis. Other apolipoproteins are known to be closely associated with amyloid fibrillogenesis Choi-Miura et al., 1992, Ghiso et al., 1994, Petit-Turcotte et al., 2001, Zlokovic et al., 1994. Serum amyloid A, apo AII, and apo AI are deposited as different molecular forms in systemic amyloid disorders (for review, see Ghiso et al., 1994). SPs have also been shown to contain apo J and apo D Choi-Miura et al., 1992, Navarro et al., 2001. Apo J (clusterin or SP-40) is a ubiquitous glycoprotein, capable of interacting with several molecules. In systemic and localized amyloid disorders, it is colocalized with a fibrillar deposits of amyloid. It has been postulated that apo J prevents possible misfolding and aggregation of the free A β and then modulates its transport across the blood–brain barrier Calero et al., 2000, Rosenberg et al., 1993, Zlokovic et al., 1994. Apo D is another glycoprotein that belongs to the lipocalin superfamily, whose members appear to act as transporters for a variety of small hydrophobic ligands. Despite a lack of similarity in structure, apo D has many properties in common with apo E and apo J, for example, tissue distribution and local synthesis in neurodegenerative processes (Beffert et al., 1998). Apo D is expressed in many tissues and is considered a multiligand–multifunctional protein (Milne et al., 1993). Apo D levels are increased in the hippocampus of AD patients, and the presence of apo E allele ϵ4 has been related to a major increase in that apolipoprotein Belloir et al., 2001, Terrisse et al., 1998. This fact, associated with an approximately 50% increase in apo D levels in apo E-deficient mice, led Terrisse et al. (1999) to propose a role for apo D as a compensatory mechanism in maintaining cellular functions. In addition, high levels of apo D have been found at sites of peripheral nerve regeneration, in degenerative nerve tissues following experimental injury, and in neuropathologies. It has been proposed that its presence in these tissues could be linked to the redistribution of lipids in growth and maintenance of neuronal membranes after injury (Rassart et al., 2000).

In the present work, we describe our studies of the regional distribution of apo D in congophilic A β deposits, and compare it to that of apo E in both AD and CAA human brains, using immunocytological and histochemical methods.

Section snippets

Materials and methods

Twenty-two human brains, from 12 patients (8 females, 4 males, aged 70.2±10 years) with AD and 10 patients (6 females, 4 males, aged 75.1±7.2 years) with CAA, were provided by the Pathology Department of The Central Hospital of Asturias and used in the present study. AD patients had been clinically diagnosed and their pathology was confirmed, postmortem, using the CERAD criteria (Mirra et al., 1991). Pieces of cerebral cortex (frontal and parietal), striatum, and hippocampus were obtained at

Results

Immunocytochemical studies revealed apo E and apo D immunoreactivity in all brain sections sampled. The immunoreactivity of apo D was present in some vessels, oligodendrocytes, astrocytes, and neurons and also in amyloid deposits. In contrast, apo E immunoreactivity was located mainly in amyloid deposits, although it could be found in some astrocytes. The labeling for apo E was more similar to Congo Red staining than the labeling observed for apo D. Extracellular and intracellular NFTs were

Discussion

In the present work, apo D has been localized in relation to all types of amyloid deposits. Previously, our group reported that apo D immunoreactivity was present in SPs in elderly and AD patients (Navarro et al., 2001). These findings are confirmed in the present work, and the localization of apo D in relation to cerebrovascular amyloid deposits is described. Apo D expression is observed in DPs and NPs, which show strong immunoreactivity in swollen neurites and around amyloid cores. Other

Acknowledgements

This work was supported by grants from Fondo de Investigación Sanitaria Española (02-PI020324 and 03-RED-C03/06).

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