Limits...
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

Increased cerebral capillary amyloid deposition in bigenic Tg-SwDI/Tg2576 mouse brain.Transgenic mouse brain sections (from 6 to 18 months old) were stained for fibrillar amyloid using thioflavin S (green) and immunolabelled for cerebral blood vessels using an antibody to collagen IV (red). (a–c) Tg-SwDI mice; (d–f) Tg2576 mice; and (g–i) bigenic Tg-SwDI/Tg2576 mice. Scale bar, 25 μm. Transgenic mouse brain sections (from 18 months old) were stained for fibrillar amyloid using thioflavin S and immunolabelled for cerebral blood vessels using an antibody to collagen IV. (j) The area occupied by parenchymal fibrillar amyloid plaques was determined in specific brain regions of each transgenic mouse line using stereological principles as described in Methods. The data presented are the mean±s.d. of 4–6 mice per group. (k) The frequency of cerebral capillary amyloid was determined in specific brain regions of each transgenic mouse line using stereological principles as described in Methods. The data presented are the mean±s.d. of 4–6 mice per group. (l) Microvessels exhibiting amyloid deposition were selected from distinct brain regions of each transgenic mouse line and the volume of microvascular amyloid was determined as described in Methods. The data presented are the mean±s.d. of a total of 50 microvessels selected from each brain region of three mice per group. 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
getmorefigures.php?uid=PMC5121328&req=5

f4: Increased cerebral capillary amyloid deposition in bigenic Tg-SwDI/Tg2576 mouse brain.Transgenic mouse brain sections (from 6 to 18 months old) were stained for fibrillar amyloid using thioflavin S (green) and immunolabelled for cerebral blood vessels using an antibody to collagen IV (red). (a–c) Tg-SwDI mice; (d–f) Tg2576 mice; and (g–i) bigenic Tg-SwDI/Tg2576 mice. Scale bar, 25 μm. Transgenic mouse brain sections (from 18 months old) were stained for fibrillar amyloid using thioflavin S and immunolabelled for cerebral blood vessels using an antibody to collagen IV. (j) The area occupied by parenchymal fibrillar amyloid plaques was determined in specific brain regions of each transgenic mouse line using stereological principles as described in Methods. The data presented are the mean±s.d. of 4–6 mice per group. (k) The frequency of cerebral capillary amyloid was determined in specific brain regions of each transgenic mouse line using stereological principles as described in Methods. The data presented are the mean±s.d. of 4–6 mice per group. (l) Microvessels exhibiting amyloid deposition were selected from distinct brain regions of each transgenic mouse line and the volume of microvascular amyloid was determined as described in Methods. The data presented are the mean±s.d. of a total of 50 microvessels selected from each brain region of three mice per group. Pair-wise comparisons were made using t-test and significant differences (P<0.05) are indicated and limited to three decimal places.

Mentions: To specifically identify fibrillar amyloid deposition in the brains of the different mice we performed thioflavin S staining. Examination of the brain tissues revealed striking differences in the compartmental pattern of fibrillar amyloid deposition. Tg-SwDI mice, from 6 months of age on, showed the characteristic pattern of progressive accumulation of fibrillar amyloid in the form of small punctate deposits primarily along cerebral capillaries (Fig. 4a–c). In contrast, Tg2576 mice showed no appreciable fibrillar amyloid deposition at 6 months of age (Fig. 4d). However, as the Tg2576 mice continued to age there was progressive accumulation of primarily large, fibrillar amyloid parenchymal plaques, but no appreciable microvascular amyloid (Fig. 4e,f). On the other hand, the bigenic Tg-SwDI/Tg2576 mice exhibited a mixed pattern of fibrillar amyloid deposition. At the early age of 6 months small capillary and parenchymal amyloid deposits appeared (Fig. 4g). As the bigenic mice continued to age from 12 to 18 months parenchymal amyloid plaques were evident but the striking feature was the notably enlarged accumulation of fibrillar amyloid around the cerebral capillaries (Fig. 4h,i).


Cerebral vascular amyloid seeds drive amyloid β -protein fibril assembly with a distinct anti-parallel structure
Increased cerebral capillary amyloid deposition in bigenic Tg-SwDI/Tg2576 mouse brain.Transgenic mouse brain sections (from 6 to 18 months old) were stained for fibrillar amyloid using thioflavin S (green) and immunolabelled for cerebral blood vessels using an antibody to collagen IV (red). (a–c) Tg-SwDI mice; (d–f) Tg2576 mice; and (g–i) bigenic Tg-SwDI/Tg2576 mice. Scale bar, 25 μm. Transgenic mouse brain sections (from 18 months old) were stained for fibrillar amyloid using thioflavin S and immunolabelled for cerebral blood vessels using an antibody to collagen IV. (j) The area occupied by parenchymal fibrillar amyloid plaques was determined in specific brain regions of each transgenic mouse line using stereological principles as described in Methods. The data presented are the mean±s.d. of 4–6 mice per group. (k) The frequency of cerebral capillary amyloid was determined in specific brain regions of each transgenic mouse line using stereological principles as described in Methods. The data presented are the mean±s.d. of 4–6 mice per group. (l) Microvessels exhibiting amyloid deposition were selected from distinct brain regions of each transgenic mouse line and the volume of microvascular amyloid was determined as described in Methods. The data presented are the mean±s.d. of a total of 50 microvessels selected from each brain region of three mice per group. 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

f4: Increased cerebral capillary amyloid deposition in bigenic Tg-SwDI/Tg2576 mouse brain.Transgenic mouse brain sections (from 6 to 18 months old) were stained for fibrillar amyloid using thioflavin S (green) and immunolabelled for cerebral blood vessels using an antibody to collagen IV (red). (a–c) Tg-SwDI mice; (d–f) Tg2576 mice; and (g–i) bigenic Tg-SwDI/Tg2576 mice. Scale bar, 25 μm. Transgenic mouse brain sections (from 18 months old) were stained for fibrillar amyloid using thioflavin S and immunolabelled for cerebral blood vessels using an antibody to collagen IV. (j) The area occupied by parenchymal fibrillar amyloid plaques was determined in specific brain regions of each transgenic mouse line using stereological principles as described in Methods. The data presented are the mean±s.d. of 4–6 mice per group. (k) The frequency of cerebral capillary amyloid was determined in specific brain regions of each transgenic mouse line using stereological principles as described in Methods. The data presented are the mean±s.d. of 4–6 mice per group. (l) Microvessels exhibiting amyloid deposition were selected from distinct brain regions of each transgenic mouse line and the volume of microvascular amyloid was determined as described in Methods. The data presented are the mean±s.d. of a total of 50 microvessels selected from each brain region of three mice per group. Pair-wise comparisons were made using t-test and significant differences (P<0.05) are indicated and limited to three decimal places.
Mentions: To specifically identify fibrillar amyloid deposition in the brains of the different mice we performed thioflavin S staining. Examination of the brain tissues revealed striking differences in the compartmental pattern of fibrillar amyloid deposition. Tg-SwDI mice, from 6 months of age on, showed the characteristic pattern of progressive accumulation of fibrillar amyloid in the form of small punctate deposits primarily along cerebral capillaries (Fig. 4a–c). In contrast, Tg2576 mice showed no appreciable fibrillar amyloid deposition at 6 months of age (Fig. 4d). However, as the Tg2576 mice continued to age there was progressive accumulation of primarily large, fibrillar amyloid parenchymal plaques, but no appreciable microvascular amyloid (Fig. 4e,f). On the other hand, the bigenic Tg-SwDI/Tg2576 mice exhibited a mixed pattern of fibrillar amyloid deposition. At the early age of 6 months small capillary and parenchymal amyloid deposits appeared (Fig. 4g). As the bigenic mice continued to age from 12 to 18 months parenchymal amyloid plaques were evident but the striking feature was the notably enlarged accumulation of fibrillar amyloid around the cerebral capillaries (Fig. 4h,i).

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