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Cerebral vascular amyloid seeds drive amyloid β -protein fibril assembly with a distinct anti-parallel structure

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ABSTRACT

Cerebrovascular accumulation of amyloid β-protein (Aβ), a condition known as cerebral amyloid angiopathy (CAA), is a common pathological feature of patients with Alzheimer's disease. Familial Aβ mutations, such as Dutch-E22Q and Iowa-D23N, can cause severe cerebrovascular accumulation of amyloid that serves as a potent driver of vascular cognitive impairment and dementia. The distinctive features of vascular amyloid that underlie its unique pathological properties remain unknown. Here, we use transgenic mouse models producing CAA mutants (Tg-SwDI) or overproducing human wild-type Aβ (Tg2576) to demonstrate that CAA-mutant vascular amyloid influences wild-type Aβ deposition in brain. We also show isolated microvascular amyloid seeds from Tg-SwDI mice drive assembly of human wild-type Aβ into distinct anti-parallel β-sheet fibrils. These findings indicate that cerebrovascular amyloid can serve as an effective scaffold to promote rapid assembly and strong deposition of Aβ into a unique structure that likely contributes to its distinctive pathology.

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Progressive accumulation of Aβ in transgenic mouse brains.Representative images of 6–18-month-old transgenic mouse brain sections were immunostained for Aβ (brown) as described in Methods. (a–d) Tg-SwDI mice; (e–h) Tg2576 mice; and (i–l) bigenic Tg-SwDI/Tg2576 mice. High-magnification images show vascular deposits (white arrows) and parenchymal plaques (black arrows). Scale bars: low mag, 1 mm; high mag, 50 μm.
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f3: Progressive accumulation of Aβ in transgenic mouse brains.Representative images of 6–18-month-old transgenic mouse brain sections were immunostained for Aβ (brown) as described in Methods. (a–d) Tg-SwDI mice; (e–h) Tg2576 mice; and (i–l) bigenic Tg-SwDI/Tg2576 mice. High-magnification images show vascular deposits (white arrows) and parenchymal plaques (black arrows). Scale bars: low mag, 1 mm; high mag, 50 μm.

Mentions: The analysis of cerebral human Aβ deposition by immunolabelling showed that at 6 months of age Tg-SwDI mice and bigenic Tg-SwDI/Tg2576 mice exhibited early stage Aβ deposition most prominent in the subiculum region (Fig. 3a,i, respectively), whereas the Tg2576 mice showed little, if any, Aβ deposition at this age (Fig. 3e). However, as all three lines of mice aged from 12 to 18 months the accumulation of deposited Aβ increased dramatically and was most robust in the bigenic Tg-SwDI/Tg2576 mice, reflecting the Aβ ELISA results (Supplementary Fig. 6). Higher magnification images at 18 months showed that Tg-SwDI mice exhibited numerous small, dense deposits along cerebral capillaries and abundant diffuse Aβ deposits in the surrounding brain parenchyma (Fig. 3d), consistent with previous findings2223. In contrast, Tg2576 mice showed large, dense parenchymal Aβ plaques (Fig. 3h), while bigenic Tg-SwDI/Tg2576 mice displayed a mixture of parenchymal Aβ plaques and, notably, greatly enlarged Aβ deposits along the capillaries (Fig. 3l).


Cerebral vascular amyloid seeds drive amyloid β -protein fibril assembly with a distinct anti-parallel structure
Progressive accumulation of Aβ in transgenic mouse brains.Representative images of 6–18-month-old transgenic mouse brain sections were immunostained for Aβ (brown) as described in Methods. (a–d) Tg-SwDI mice; (e–h) Tg2576 mice; and (i–l) bigenic Tg-SwDI/Tg2576 mice. High-magnification images show vascular deposits (white arrows) and parenchymal plaques (black arrows). Scale bars: low mag, 1 mm; high mag, 50 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5121328&req=5

f3: Progressive accumulation of Aβ in transgenic mouse brains.Representative images of 6–18-month-old transgenic mouse brain sections were immunostained for Aβ (brown) as described in Methods. (a–d) Tg-SwDI mice; (e–h) Tg2576 mice; and (i–l) bigenic Tg-SwDI/Tg2576 mice. High-magnification images show vascular deposits (white arrows) and parenchymal plaques (black arrows). Scale bars: low mag, 1 mm; high mag, 50 μm.
Mentions: The analysis of cerebral human Aβ deposition by immunolabelling showed that at 6 months of age Tg-SwDI mice and bigenic Tg-SwDI/Tg2576 mice exhibited early stage Aβ deposition most prominent in the subiculum region (Fig. 3a,i, respectively), whereas the Tg2576 mice showed little, if any, Aβ deposition at this age (Fig. 3e). However, as all three lines of mice aged from 12 to 18 months the accumulation of deposited Aβ increased dramatically and was most robust in the bigenic Tg-SwDI/Tg2576 mice, reflecting the Aβ ELISA results (Supplementary Fig. 6). Higher magnification images at 18 months showed that Tg-SwDI mice exhibited numerous small, dense deposits along cerebral capillaries and abundant diffuse Aβ deposits in the surrounding brain parenchyma (Fig. 3d), consistent with previous findings2223. In contrast, Tg2576 mice showed large, dense parenchymal Aβ plaques (Fig. 3h), while bigenic Tg-SwDI/Tg2576 mice displayed a mixture of parenchymal Aβ plaques and, notably, greatly enlarged Aβ deposits along the capillaries (Fig. 3l).

View Article: PubMed Central - PubMed

ABSTRACT

Cerebrovascular accumulation of amyloid β-protein (Aβ), a condition known as cerebral amyloid angiopathy (CAA), is a common pathological feature of patients with Alzheimer's disease. Familial Aβ mutations, such as Dutch-E22Q and Iowa-D23N, can cause severe cerebrovascular accumulation of amyloid that serves as a potent driver of vascular cognitive impairment and dementia. The distinctive features of vascular amyloid that underlie its unique pathological properties remain unknown. Here, we use transgenic mouse models producing CAA mutants (Tg-SwDI) or overproducing human wild-type Aβ (Tg2576) to demonstrate that CAA-mutant vascular amyloid influences wild-type Aβ deposition in brain. We also show isolated microvascular amyloid seeds from Tg-SwDI mice drive assembly of human wild-type Aβ into distinct anti-parallel β-sheet fibrils. These findings indicate that cerebrovascular amyloid can serve as an effective scaffold to promote rapid assembly and strong deposition of Aβ into a unique structure that likely contributes to its distinctive pathology.

No MeSH data available.


Related in: MedlinePlus