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The coarse-grained plaque: a divergent A? plaque-type in early-onset Alzheimer's disease.

ABSTRACT: Alzheimer's disease (AD) is characterized by amyloid-beta (A?) deposits, which come in myriad morphologies with varying clinical relevance. Previously, we observed an atypical A? deposit, referred to as the coarse-grained plaque. In this study, we evaluate the plaque's association with clinical disease and perform in-depth immunohistochemical and morphological characterization. The coarse-grained plaque, a relatively large (Ø???80 µm) deposit, characterized as having multiple cores and A?-devoid pores, was prominent in the neocortex. The plaque was semi-quantitatively scored in the middle frontal gyrus of A?-positive cases (n?=?74), including non-demented cases (n?=?15), early-onset (EO)AD (n?=?38), and late-onset (LO)AD cases (n?=?21). The coarse-grained plaque was only observed in cases with clinical dementia and more frequently present in EOAD compared to LOAD. This plaque was associated with a homozygous APOE ?4 status and cerebral amyloid angiopathy (CAA). In-depth characterization was done by studying the coarse-grained plaque's neuritic component (pTau, APP, PrPC), A? isoform composition (A?40, A?42, A?N3pE, pSer8A?), its neuroinflammatory component (C4b, CD68, MHC-II, GFAP), and its vascular attribution (laminin, collagen IV, norrin). The plaque was compared to the classic cored plaque, cotton wool plaque, and CAA. Similar to CAA but different from classic cored plaques, the coarse-grained plaque was predominantly composed of A?40. Furthermore, the coarse-grained plaque was distinctly associated with both intense neuroinflammation and vascular (capillary) pathology. Confocal laser scanning microscopy (CLSM) and 3D analysis revealed for most coarse-grained plaques a particular A?40 shell structure and a direct relation with vessels. Based on its morphological and biochemical characteristics, we conclude that the coarse-grained plaque is a divergent A? plaque-type associated with EOAD. Differences in A? processing and aggregation, neuroinflammatory response, and vascular clearance may presumably underlie the difference between coarse-grained plaques and other A? deposits. Disentangling specific A? deposits between AD subgroups may be important in the search for disease-mechanistic-based therapies.

SUBMITTER: Boon BDC

PROVIDER: S-EPMC7666300 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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The coarse-grained plaque: a divergent Aβ plaque-type in early-onset Alzheimer's disease.

Boon Baayla D C BDC Bulk Marjolein M Jonker Allert J AJ Morrema Tjado H J THJ van den Berg Emma E Popovic Marko M Walter Jochen J Kumar Sathish S van der Lee Sven J SJ Holstege Henne H Zhu Xiaoyue X Van Nostrand William E WE Natté Remco R van der Weerd Louise L Bouwman Femke H FH van de Berg Wilma D J WDJ Rozemuller Annemieke J M AJM Hoozemans Jeroen J M JJM

Acta neuropathologica 20200914 6

Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) deposits, which come in myriad morphologies with varying clinical relevance. Previously, we observed an atypical Aβ deposit, referred to as the coarse-grained plaque. In this study, we evaluate the plaque's association with clinical disease and perform in-depth immunohistochemical and morphological characterization. The coarse-grained plaque, a relatively large (Ø ≈ 80 µm) deposit, characterized as having multiple cores and Aβ-devoid ...[more]

PMID: 32926214

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Project description:The growth mechanism of β-amyloid (Aβ) peptide fibrils was studied by a physics-based coarse-grained united-residue model and molecular dynamics (MD) simulations. To identify the mechanism of monomer addition to an Aβ(1-40) fibril, we placed an unstructured monomer at a distance of 20 Å from a fibril template and allowed it to interact freely with the latter. The monomer was not biased towards fibril conformation by either the force field or the MD algorithm. With the use of a coarse-grained model with replica-exchange molecular dynamics, a longer timescale was accessible, making it possible to observe how the monomers probe different binding modes during their search for the fibril conformation. Although different assembly pathways were seen, they all follow a dock-lock mechanism with two distinct locking stages, consistent with experimental data on fibril elongation. Whereas these experiments have not been able to characterize the conformations populating the different stages, we have been able to describe these different stages explicitly by following free monomers as they dock onto a fibril template and to adopt the fibril conformation (i.e., we describe fibril elongation step by step at the molecular level). During the first stage of the assembly ("docking"), the monomer tries different conformations. After docking, the monomer is locked into the fibril through two different locking stages. In the first stage, the monomer forms hydrogen bonds with the fibril template along one of the strands in a two-stranded β-hairpin; in the second stage, hydrogen bonds are formed along the second strand, locking the monomer into the fibril structure. The data reveal a free-energy barrier separating the two locking stages. The importance of hydrophobic interactions and hydrogen bonds in the stability of the Aβ fibril structure was examined by carrying out additional canonical MD simulations of oligomers with different numbers of chains (4-16 chains), with the fibril structure as the initial conformation. The data confirm that the structures are stabilized largely by hydrophobic interactions and show that intermolecular hydrogen bonds are highly stable and contribute to the stability of the oligomers as well.

Dataset Information

The coarse-grained plaque: a divergent A? plaque-type in early-onset Alzheimer's disease.

Publications

The coarse-grained plaque: a divergent Aβ plaque-type in early-onset Alzheimer's disease.

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