Aβプラークの新しいタイプーcoarse-grained plaqueー

アルツハイマー病（Alzheimer's disease, AD）の２大病理といえば、

アミロイドβ（Aβ）プラークと神経原線維変化（NFT）ですが、

Aβプラークには、その形態や構成Aβによって、いくつかの種類に分類されていました [1]。

  • Fibrillar plaques : 30–100 µm, Aβ+, 認知機能との相関あり
    • compact / cored-only plaques
    • classic cored plaques
    • Non-fibrillar plaques (diffuse plaques) : 10 to >100 µm. 認知機能と相関なし
    • Cotton wool plaques : PSEN1変異のAD脳病理に特有

また、Aβは血管にも沈着し（cerebral amyloid angiopathy, CAA）、

その沈着する血管の種類によって2種類に分類されていました [2, 3]。

  • CAA-type 1 : 毛細血管（＋通常の動脈、細動脈）にも沈着
  • CAA-type 2 : 動脈や細動脈のみに沈着

 

一昨年、オランダ・VU大学メディカルセンターのDr. Boonらの研究グループは、AD病理の中に、上記に分類されない、Aβプラークがあることを報告しました [4]。

今回、同研究グループは、この ”非典型的な” Aβプラークについて詳しく調べ、その特徴を報告しました [5]。

The coarse-grained plaque: a divergent Aβ plaque-type in early-onset Alzheimer’s disease
https://link.springer.com/article/10.1007/s00401-020-02198-8
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.

Aβプラークの新しいタイプーcoarse-grained plaqueー

彼らは、このAβプラークを 「coarse-grained plaeue」と名付けた。

coarse-grained plaqueの特徴としては、

  • ~80 µmとやや大きめ
  • 多数のコアと、孔をもち、大脳皮質に多い
  • 早期発症型ADに多い
  • APOE4+/+, CAAと相関あり
  • リン酸化タウ、APP、PrPc等、神経突起を含む
  • 炎症細胞の集簇あり
  • 血管成分の関与あり
  • 主にAβ40で構成されている

coarse-grained-plaques-2

coarse-grained-plaques-3

という感じで、

  • Aβプラークだけれども、cored plaquesやcotton plaquesとの共通点／相違点をそれぞれ持つ
  • ある程度CAA type-1との共通点が多い

という特徴をもつcoarse-grained plaqueは、

今まで報告されてきたAβプラークと異なるタイプのAβプラークといえる。

coarse-grained-plaques-4

References

  1. Alafuzoff I, Thal DR, Arzberger T, Bogdanovic N, Al-Sarraj S, Bodi I, Boluda S, Bugiani O, Duyckaerts C, Gelpi E, Gentleman S, Giaccone G, Graeber M, Hortobagyi T, Höftberger R, Ince P, Ironside JW, Kavantzas N, King A, Korkolopoulou P, Kovács GG, Meyronet D, Monoranu C, Nilsson T, Parchi P, Patsouris E, Pikkarainen M, Revesz T, Rozemuller A, Seilhean D, Schulz-Schaeffer W, Streichenberger N, Wharton SB, Kretzschmar H. Assessment of beta-amyloid deposits in human brain: a study of the BrainNet Europe Consortium. Acta Neuropathol. 2009 Mar;117(3):309-20. doi: 10.1007/s00401-009-0485-4. Epub 2009 Feb 1. PMID:19184666; PMCID: PMC2910889.
  2. Mäkelä M, Paetau A, Polvikoski T, Myllykangas L, Tanskanen M. Capillary amyloid-β protein deposition in a population-based study (Vantaa 85+). J Alzheimers Dis. 2016;49(1):149-57. doi: 10.3233/JAD-150241. PMID:26444758.
  3. Hondius DC, Eigenhuis KN, Morrema THJ, van der Schors RC, van Nierop P, Bugiani M, Li KW, Hoozemans JJM, Smit AB, Rozemuller AJM. Proteomics analysis identifies new markers associated with capillary cerebral amyloid angiopathy in Alzheimer's disease. Acta Neuropathol Commun. 2018 Jun 4;6(1):46. doi: 10.1186/s40478-018-0540-2. PMID:29860944; PMCID: PMC5985582.
  4. Boon BDC, Hoozemans JJM, Lopuhaä B, Eigenhuis KN, Scheltens P, Kamphorst W, Rozemuller AJM, Bouwman FH. Neuroinflammation is increased in the parietal cortex of atypical Alzheimer's disease. J Neuroinflammation. 2018 May 29;15(1):170. doi: 10.1186/s12974-018-1180-y. PMID:29843759; PMCID: PMC5975447.
  5. Boon BDC, Bulk M, Jonker AJ, Morrema THJ, van den Berg E, Popovic M, Walter J, Kumar S, van der Lee SJ, Holstege H, Zhu X, Van Nostrand WE, Natté R, van der Weerd L, Bouwman FH, van de Berg WDJ, Rozemuller AJM, Hoozemans JJM. The coarse-grained plaque: a divergent Aβ plaque-type in early-onset Alzheimer's disease. Acta Neuropathol. 2020 Sep 14. doi: 10.1007/s00401-020-02198-8. Epub ahead of print. PMID:32926214.
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