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Updated: Jun 3, 2025
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Published on: November 30, 2018
Aβ40 Fibril Assembly on Human Cerebral Smooth Muscle Cells Impairs Cell Viability
Brandon Irizarry1, Judianne Davis2, Jitika Rajpoot1
1Center for Structural Biology, Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York 11794-5215, United States.
Insights
Cerebral amyloid angiopathy (CAA) involves amyloid-β (Aβ) peptide buildup in brain vessels. This study shows fibrillar Aβ seeds promote new amyloid formation on smooth muscle cells, causing cell death and advancing disease.
Area of Science:
- Neuroscience
- Biochemistry
- Cell Biology
Background:
- Cerebral amyloid angiopathy (CAA) is linked to brain hemorrhaging and cognitive decline in Alzheimer's disease (AD) and vascular cognitive impairment and dementia (VCID).
- Familial mutations in amyloid-β (Aβ) peptide at positions 22 and 23 accelerate CAA pathology.
- Human cerebral smooth muscle (HCSM) cells are key sites for amyloid deposition in cerebral blood vessels.
Purpose of the Study:
- To investigate the impact of fibrillar Aβ peptides on HCSM cell viability.
- To compare the effects of familial mutant Aβ40 (Dutch) with wild-type Aβ40 and Aβ42.
Main Methods:
- Primary cultures of HCSM cells were treated with monomeric and fibrillar forms of Aβ peptides.
- Cell viability was assessed after exposure to different Aβ variants and fibril seeds.
- Intrathecal administration of Aβ40-Dutch fibrillar seeds was performed in a transgenic rat model of CAA.
Main Results:
- Monomeric Aβ40-Dutch and Aβ42-WT significantly reduced HCSM cell viability, while Aβ40-WT was less toxic.
- Aβ fibrils from sporadic or familial CAA did not significantly decrease HCSM cell viability upon direct binding.
- Coincubation of Aβ40-WT monomers with sporadic CAA fibrils significantly reduced cell viability and increased cell surface fibril formation.
- Intrathecal Aβ40-Dutch seeds promoted fibrillar amyloid accumulation in meningeal vessel smooth muscle in rats.
Conclusions:
- Fibrillar Aβ seeds can propagate new amyloid fibril expansion on cerebral vascular smooth muscle.
- This process leads to membrane disruption and HCSM cell death.
- The findings suggest a mechanism for CAA progression involving seed-mediated amyloid expansion and vascular damage.
Abstract:
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.
