Elsevier

Peptides

Volume 23, Issue 7, July 2002, Pages 1343-1350
Peptides

Senile plaque composition and posttranslational modification of amyloid-β peptide and associated proteins

https://doi.org/10.1016/S0196-9781(02)00070-0Get rights and content

Abstract

Amyloid deposits are primarily composed of the amyloid-β protein, although other proteins (and metal ions) also have been colocalized to these lesions. The pattern of oxidative modifications in amyloid plaques is very different to that associated with neurofibrillary tangles and neuronal cell bodies, likely reflecting the different composition of these structures, accessibility of oxidants, the generation of oxidants in and around these structures and the intrinsic antioxidant defense systems to protect these structures. Future studies directed at understanding interactions with other amyloid components, the role of oxidative modifications in stabilizing amyloid deposits and the determination of protease cleavage sites on Aβ may provide mechanistic insights regarding both amyloid formation and removal.

Introduction

Neuronal amyloidoses, found in Alzheimer disease (AD) [47], [84], Down syndrome [48], head injury [107] and in healthy individuals [30], are characterized by the extracellular deposition of a 39–43 amino acid protein, amyloid-β (Aβ), derived from the larger amyloid-β protein precursor (AβPP). AβPP is processed in the brain by two competing pathways that involve different proteolytic enzymes that were initially termed secretases (α-, β- and γ-secretases). These pathways either promote the generation of Aβ (amyloidogenic pathway) or preclude its production (non-amyloidogenic pathway) [124]. Aβ is released as a soluble product [50], [69] from AβPP [50], [69], [145] via a series of metabolic cleavage steps through the combined actions of β- and γ-secretases [49]. β-Secretase was recently identified as a transmembrane aspartyl protease known as BACE (beta-site AβPP cleavage enzyme) [59], [125], [148], [155]. Defective processing of the β-secretase digested AβPP fragment by presenilin-1-deficient (PS-1) mice, a gene associated with early onset AD, has suggested that PS1 may be the γ-secretase, or is at least an important factor in the regulation of γ-secretase proteolytic activity [40], [75], [76], [154]. PS-1 is an integral membrane protein that resides predominantly in intracellular membranous organelles such as the endoplasmic reticulum and Golgi apparatus which are also the identified sites of AβPP processing [31], [74]. Although Aβ is released as a soluble protein, and is detected in biological fluids and tissue, it aggregates as diffuse amorphous (noncongophilic) deposits and dense, focal (congophilic), extracellular deposits in AD [47], [48], [84]. The deposition of Aβ and numerous other components, into amyloid deposits, is associated with a chronic inflammatory response and oxidative damage (reviewed in [9], [93]). In this article, we review the composition of amyloid plaques, and the posttranslational modification of these components. Readers are directed to other recent reviews for information on the mechanisms of amyloid formation and clearance [5], [9], [38], [99].

Section snippets

Amyloid plaque neuropathology

Aβ deposits are characterized histologically as ‘diffuse’, primitive, neuritic and cored or compact amyloid plaques (reviewed in [127]). A recent study of plaque dynamics, using in vivo multiphoton microscopy, showed that there is no change in the size of plaques reimaged over time in Tg2576 AβPP-transgenic mice [25], indicating a dynamic model of continual deposition and asymmetrical plaque clearance in which plaques reach a stable size and stop growing. It has been proposed that such diffuse

Amyloid plaque composition

While amyloid plaques are primarily composed of the Aβ protein, a host of other compounds have been colocalized with Aβ in the AD brain. Biochemical, immunochemical, amino acid analysis, protein sequencing and analytical methods have demonstrated an association with the following components:

  • 1.

    Proteoglycans, including heparan, chondroitin, keratin and dermatan sulphate proteoglycans [18], [32], [67], [98], [101], [123], [135], [136], [137], [138], [139].

  • 2.

    Inflammatory molecules, including acute

Posttranslational modifications of amyloid deposits

Posttranslational modifications detected in proteins that deposit in amyloid plaques in the AD brain include advanced glycation endproducts [152], such as pyrraline [130], pyroglutamated and racemized amino acids [88], [110], [118], dityrosine [6] and reactive carbonyls (Atwood et al., unpublished results). Pentosidine and 4-hydroxynonenal (HNE) derived advanced lipid peroxidation end products also have been localized together with iron in amyloid deposits of ‘Hsiao’ transgenic mice [134].

Topology of amyloid oxidative modifications in brain

The effects of posttranslational modifications of Aβ and other components on the stabilization of amyloid plaques remains unclear. However, covalent crosslinking and pyroglutamate blockage of Aβ residues would be expected to hinder normal proteolytic processes. In support of this point, the oxidative modifications observed in amyloid plaques such as pyroglutamate, racemized amino acids and dityrosine are all markers of long-lived proteins, typically found in structural proteins.

The

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