Department of Biological Sciences, Markey Center for Structural Biology, Purdue University, West Lafayette, IN, 47906, USA.
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, 635 Barnhill Dr., MSB A136, Indianapolis, IN, 46202, USA.
Acta Neuropathol. 2024 Aug 15;148(1):20. doi: 10.1007/s00401-024-02786-y.
Cotton wool plaques (CWPs) have been described as features of the neuropathologic phenotype of dominantly inherited Alzheimer disease (DIAD) caused by some missense and deletion mutations in the presenilin 1 (PSEN1) gene. CWPs are round, eosinophilic amyloid-β (Aβ) plaques that lack an amyloid core and are recognizable, but not fluorescent, in Thioflavin S (ThS) preparations. Amino-terminally truncated and post-translationally modified Aβ peptide species are the main component of CWPs. Tau immunopositive neurites may be present in CWPs. In addition, neurofibrillary tangles coexist with CWPs. Herein, we report the structure of Aβ and tau filaments isolated from brain tissue of individuals affected by DIAD caused by the PSEN1 V261I and A431E mutations, with the CWP neuropathologic phenotype. CWPs are predominantly composed of type I Aβ filaments present in two novel arrangements, type Ic and type Id; additionally, CWPs contain type I and type Ib Aβ filaments. Tau filaments have the AD fold, which has been previously reported in sporadic AD and DIAD. The formation of type Ic and type Id Aβ filaments may be the basis for the phenotype of CWPs. Our data are relevant for the development of PET imaging methodologies to best detect CWPs in DIAD.
棉绒斑（Cotton wool plaques，CWPs）已被描述为某些早老素 1（presenilin 1，PSEN1）基因突变引起的显性遗传性阿尔茨海默病（dominantly inherited Alzheimer disease，DIAD）的神经病理学表型特征。CWPs 是圆形、嗜酸性淀粉样β（amyloid-β，Aβ）斑块，缺乏淀粉样核心，在噻唑黄素 S（Thioflavin S，ThS）制剂中可识别但不发荧光。氨基末端截断和翻译后修饰的 Aβ肽是 CWPs 的主要成分。CWP 中可能存在 Tau 免疫阳性神经突。此外，神经原纤维缠结与 CWPs 共存。在此，我们报告了由 PSEN1 V261I 和 A431E 突变引起的 DIAD 患者脑组织中分离的 Aβ和 Tau 纤维的结构，其具有 CWP 神经病理学表型。CWPs 主要由两种新型排列的 I 型 Aβ纤维组成，即 Ic 型和 Id 型；此外，CWP 还含有 I 型和 Ib 型 Aβ纤维。Tau 纤维具有 AD 折叠，这在散发性 AD 和 DIAD 中已有报道。Ic 型和 Id 型 Aβ纤维的形成可能是 CWP 表型的基础。我们的数据与开发 PET 成像方法学以最佳检测 DIAD 中的 CWPs 相关。
