The coarse-grained plaque: a divergent A\u03b2 plaque-type in early-onset Alzheimer\u2019s disease

Baayla D C Boon,Xiaoyue Zhu,Allert J Jonker,Femke H Bouwman,William E Van Nostrand,Jochen Walter,Sven J Van Der Lee,Emma Van Den Berg,Jeroen J M Hoozemans,Marjolein Bulk,Tjado H J Morrema,Wilma D J Van De Berg,Marko Popovic,Louise Van Der Weerd,Remco Natté,Annemieke J M Rozemuller,Sathish Kumar,Henne Holstege

doi:10.1007/s00401-020-02198-8

Abstract

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 pores, was prominent in the neocortex. The plaque was semi-quantitatively scored in the middle frontal gyrus of Aβ-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 ε4 status and cerebral amyloid angiopathy (CAA). In-depth characterization was done by studying the coarse-grained plaque’s neuritic component (pTau, APP, PrPC), Aβ isoform composition (Aβ40, Aβ42, AβN3pE, pSer8Aβ), 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 Aβ40. 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 Aβ40 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 Aβ plaque-type associated with EOAD. Differences in Aβ processing and aggregation, neuroinflammatory response, and vascular clearance may presumably underlie the difference between coarse-grained plaques and other Aβ deposits. Disentangling specific Aβ deposits between AD subgroups may be important in the search for disease-mechanistic-based therapies.

Highlights

Amyloid-beta (Aβ) plaques and hyperphosphorylated tau tangles are the main pathological hallmarks of Alzheimer’s disease (AD)
Disentangling specific Aβ deposits between AD subgroups may be important in the search for disease-mechanistic-based therapies
A few coarse-grained plaques were observed in the olivary nuclei and in another case one coarse-grained plaque was seen in the cerebellum

Summary

Introduction

Amyloid-beta (Aβ) plaques and hyperphosphorylated tau (pTau) tangles are the main pathological hallmarks of Alzheimer’s disease (AD). Aβ plaques originate from the accumulation and aggregation of the Aβ peptide, which is formed by the sequential cleavage of the amyloid precursor protein by β- and γ-secretases [21]. The Aβ peptide can undergo several post-translational modifications resulting, e.g., in truncated pyroglutamate Aβ (AβN3pE) and Aβ phosphorylated at serine 8 (pSer8Aβ) [30,31,32]. These different Aβ isoforms are associated with clinical disease progression and are considered to mark sequential phases of plaque and CAA maturation [20, 43, 52]

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