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

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

Quantitative immunohistochemical analysis of cerebral Aβ40 and Aβ42 deposition in the different transgenic mice.Brain sections obtained from the different transgenic mouse lines at 18 months of age were double immunolabelled for Aβ40 (red) (a–d) and Aβ42 (green) (e–h) and images were merged (i–l). Scale bars, 20 μm. (m) The levels of Aβ40 and Aβ42 in parenchymal plaque and capillary deposits were determined in the different transgenic lines and expressed as the ratio of Aβ40:Aβ42. The data presented are the mean±s.d. of 15 deposits per each line of mice. Pair-wise comparisons were made using t-test and significant differences (P<0.05) are indicated and limited to three decimal places.
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f5: Quantitative immunohistochemical analysis of cerebral Aβ40 and Aβ42 deposition in the different transgenic mice.Brain sections obtained from the different transgenic mouse lines at 18 months of age were double immunolabelled for Aβ40 (red) (a–d) and Aβ42 (green) (e–h) and images were merged (i–l). Scale bars, 20 μm. (m) The levels of Aβ40 and Aβ42 in parenchymal plaque and capillary deposits were determined in the different transgenic lines and expressed as the ratio of Aβ40:Aβ42. The data presented are the mean±s.d. of 15 deposits per each line of mice. Pair-wise comparisons were made using t-test and significant differences (P<0.05) are indicated and limited to three decimal places.

Mentions: The composition of Aβ in the vascular and parenchymal deposits in each line of mice was evaluated. First, brain sections from each line of mice were immunolabelled with antibodies specific for either Aβ40 or Aβ42 and the relative levels of each Aβ species in each type of deposit was determined. The composition of Aβ40 and Aβ42 in parenchymal plaque deposits in Tg2576 mice or bigenic Tg-SwDI/Tg2576 was essentially the same (Fig. 5). In contrast, the vascular deposits in Tg-SwDI mice contained much higher amounts of Aβ40 (≈90%) consistent with earlier reports222332. In comparison, the enlarged vascular deposits in bigenic Tg-SwDI/Tg2576 mice contained significantly higher amounts of Aβ42 than the vascular deposits in Tg-SwDI mice.


Cerebral vascular amyloid seeds drive amyloid β -protein fibril assembly with a distinct anti-parallel structure
Quantitative immunohistochemical analysis of cerebral Aβ40 and Aβ42 deposition in the different transgenic mice.Brain sections obtained from the different transgenic mouse lines at 18 months of age were double immunolabelled for Aβ40 (red) (a–d) and Aβ42 (green) (e–h) and images were merged (i–l). Scale bars, 20 μm. (m) The levels of Aβ40 and Aβ42 in parenchymal plaque and capillary deposits were determined in the different transgenic lines and expressed as the ratio of Aβ40:Aβ42. The data presented are the mean±s.d. of 15 deposits per each line of mice. Pair-wise comparisons were made using t-test and significant differences (P<0.05) are indicated and limited to three decimal places.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f5: Quantitative immunohistochemical analysis of cerebral Aβ40 and Aβ42 deposition in the different transgenic mice.Brain sections obtained from the different transgenic mouse lines at 18 months of age were double immunolabelled for Aβ40 (red) (a–d) and Aβ42 (green) (e–h) and images were merged (i–l). Scale bars, 20 μm. (m) The levels of Aβ40 and Aβ42 in parenchymal plaque and capillary deposits were determined in the different transgenic lines and expressed as the ratio of Aβ40:Aβ42. The data presented are the mean±s.d. of 15 deposits per each line of mice. Pair-wise comparisons were made using t-test and significant differences (P<0.05) are indicated and limited to three decimal places.
Mentions: The composition of Aβ in the vascular and parenchymal deposits in each line of mice was evaluated. First, brain sections from each line of mice were immunolabelled with antibodies specific for either Aβ40 or Aβ42 and the relative levels of each Aβ species in each type of deposit was determined. The composition of Aβ40 and Aβ42 in parenchymal plaque deposits in Tg2576 mice or bigenic Tg-SwDI/Tg2576 was essentially the same (Fig. 5). In contrast, the vascular deposits in Tg-SwDI mice contained much higher amounts of Aβ40 (≈90%) consistent with earlier reports222332. In comparison, the enlarged vascular deposits in bigenic Tg-SwDI/Tg2576 mice contained significantly higher amounts of Aβ42 than the vascular deposits in Tg-SwDI mice.

View Article: PubMed Central - PubMed

ABSTRACT

Cerebrovascular accumulation of amyloid &beta;-protein (A&beta;), a condition known as cerebral amyloid angiopathy (CAA), is a common pathological feature of patients with Alzheimer's disease. Familial A&beta; 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 A&beta; (Tg2576) to demonstrate that CAA-mutant vascular amyloid influences wild-type A&beta; deposition in brain. We also show isolated microvascular amyloid seeds from Tg-SwDI mice drive assembly of human wild-type A&beta; into distinct anti-parallel &beta;-sheet fibrils. These findings indicate that cerebrovascular amyloid can serve as an effective scaffold to promote rapid assembly and strong deposition of A&beta; into a unique structure that likely contributes to its distinctive pathology.

No MeSH data available.


Related in: MedlinePlus