Irizarry Brandon, Davis Judianne, Rajpoot Jitika, Zhu Xiaoyue, Xu Feng, Smith Steven O, Van Nostrand William E
Center for Structural Biology, Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York 11794-5215, United States.
George and Anne Ryan Institute for Neuroscience, Department of Biomedical and Pharmacological Sciences, University of Rhode Island, Kingston, Rhode Island 02881, United States.
Biochemistry. 2025 Mar 4;64(5):1065-1078. doi: 10.1021/acs.biochem.4c00478. Epub 2025 Jan 6.
Cerebral vascular deposition of the amyloid-β (Aβ) peptide, a condition known as cerebral amyloid angiopathy (CAA), is associated with intracerebral hemorrhaging and contributes to disease progression in Alzheimer's disease (AD) and vascular cognitive impairment and dementia (VCID). Familial mutations at positions 22 and 23 within the Aβ peptide lead to early onset and severe CAA pathology. Here, we evaluate the effects of fibrillar Aβ peptides on the viability of primary-cultured human cerebral smooth muscle (HCSM) cells, which are the major site of amyloid deposition in cerebral blood vessel walls. Comparisons are made of the familial E22Q (Dutch) mutant of Aβ40 with wild-type Aβ40 and Aβ42. In agreement with previous studies, we find that there is a significant reduction in cell viability when Aβ40-Dutch or Aβ42-WT peptides are added to HCSM cell cultures as monomeric Aβ, whereas Aβ40-WT is relatively nontoxic. The binding of Aβ fibrils derived from sporadic CAA or familial Dutch-type CAA brain tissue to the membrane surface of HCSM cells does not result in a significant loss of cell viability. In contrast, when Aβ40-WT monomers and sporadic CAA fibrils are coincubated in HCSM cell cultures, there is a significant reduction in HCSM cell viability that is accompanied by an increase in cell surface fibril formation. Lastly, intrathecal administration of Aβ40-Dutch fibrillar seeds promotes fibrillar amyloid accumulation in the smooth muscle of meningeal vessels in the rTg-D transgenic rat model of CAA. Together, the present findings suggest that fibrillar Aβ seeds propagate the expansion of new amyloid fibrils on cerebral vascular smooth muscle, leading to membrane disruption and cell death.
淀粉样β（Aβ）肽在脑血管中的沉积，即所谓的脑淀粉样血管病（CAA），与脑出血有关，并在阿尔茨海默病（AD）以及血管性认知障碍和痴呆（VCID）的疾病进展中起作用。Aβ肽第22位和23位的家族性突变会导致早发性和严重的CAA病理。在此，我们评估了纤维状Aβ肽对原代培养的人脑血管平滑肌（HCSM）细胞活力的影响，HCSM细胞是脑血管壁淀粉样沉积的主要部位。对Aβ40的家族性E22Q（荷兰型）突变体与野生型Aβ40和Aβ42进行了比较。与先前的研究一致，我们发现，当将Aβ40 - 荷兰型或Aβ42 - 野生型肽作为单体Aβ添加到HCSM细胞培养物中时，细胞活力会显著降低，而Aβ40 - 野生型相对无毒。源自散发性CAA或家族性荷兰型CAA脑组织的Aβ纤维与HCSM细胞膜表面的结合不会导致细胞活力的显著丧失。相反，当Aβ40 - 野生型单体与散发性CAA纤维在HCSM细胞培养物中共孵育时，HCSM细胞活力会显著降低，并伴有细胞表面纤维形成增加。最后，在CAA的rTg - D转基因大鼠模型中，鞘内注射Aβ40 - 荷兰型纤维种子会促进脑膜血管平滑肌中纤维状淀粉样蛋白的积累。总之，目前的研究结果表明，纤维状Aβ种子会促使新的淀粉样纤维在脑血管平滑肌上扩展，导致膜破坏和细胞死亡。
