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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.


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Dutch/Iowa CAA mutant cerebral microvascular amyloid in Tg-SwDI mice promotes the accumulation of administered biotin-labelled wild-type Aβ peptides.Biotin-labelled wild-type Aβ40 (a–c) or biotin-labelled wild-type Aβ42 (d–f) were injected into the hippocampal region of 12-month-old Tg-SwDI mice. Brain sections were prepared and fibrillar amyloid was detected using Amylo-Glo (blue) and immunolabelled with an antibody to collagen IV for detection of cerebral blood vessels (red). Biotin-labelled wild-type Aβ40 or Aβ42 peptides were detected using streptavidin-Alexa Fluor 488 (green). Scale bars, 50 μm.
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f2: Dutch/Iowa CAA mutant cerebral microvascular amyloid in Tg-SwDI mice promotes the accumulation of administered biotin-labelled wild-type Aβ peptides.Biotin-labelled wild-type Aβ40 (a–c) or biotin-labelled wild-type Aβ42 (d–f) were injected into the hippocampal region of 12-month-old Tg-SwDI mice. Brain sections were prepared and fibrillar amyloid was detected using Amylo-Glo (blue) and immunolabelled with an antibody to collagen IV for detection of cerebral blood vessels (red). Biotin-labelled wild-type Aβ40 or Aβ42 peptides were detected using streptavidin-Alexa Fluor 488 (green). Scale bars, 50 μm.

Mentions: We next investigated how wild-type Aβ peptides interact with early-onset cerebral microvascular amyloid deposits comprised of CAA mutant Aβ in vivo. Biotin-labelled human wild-type Aβ40 or Aβ42 peptides were injected into the hippocampal region of twelve months old Tg-SwDI mice, a model that exhibits prominent cerebral microvascular amyloid deposition. The injected biotin-labelled human wild-type Aβ40 (Fig. 2a–c) or Aβ42 (Fig. 2d–f) peptides showed strong and preferential accumulation on pre-existing cerebral microvascular fibrillar amyloid deposits in the surrounding tissue. No accumulations were found when biotin alone was infused into similarly aged Tg-SwDI mice or when biotin-labelled wild-type Aβ peptides were infused into similarly aged wild-type mice without microvascular CAA (Supplementary Fig. 5). These results indicate that familial CAA mutant microvascular amyloid can serve as scaffold for rapid and robust co-deposition of wild-type Aβ peptides in brain.


Cerebral vascular amyloid seeds drive amyloid β -protein fibril assembly with a distinct anti-parallel structure
Dutch/Iowa CAA mutant cerebral microvascular amyloid in Tg-SwDI mice promotes the accumulation of administered biotin-labelled wild-type Aβ peptides.Biotin-labelled wild-type Aβ40 (a–c) or biotin-labelled wild-type Aβ42 (d–f) were injected into the hippocampal region of 12-month-old Tg-SwDI mice. Brain sections were prepared and fibrillar amyloid was detected using Amylo-Glo (blue) and immunolabelled with an antibody to collagen IV for detection of cerebral blood vessels (red). Biotin-labelled wild-type Aβ40 or Aβ42 peptides were detected using streptavidin-Alexa Fluor 488 (green). Scale bars, 50 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2: Dutch/Iowa CAA mutant cerebral microvascular amyloid in Tg-SwDI mice promotes the accumulation of administered biotin-labelled wild-type Aβ peptides.Biotin-labelled wild-type Aβ40 (a–c) or biotin-labelled wild-type Aβ42 (d–f) were injected into the hippocampal region of 12-month-old Tg-SwDI mice. Brain sections were prepared and fibrillar amyloid was detected using Amylo-Glo (blue) and immunolabelled with an antibody to collagen IV for detection of cerebral blood vessels (red). Biotin-labelled wild-type Aβ40 or Aβ42 peptides were detected using streptavidin-Alexa Fluor 488 (green). Scale bars, 50 μm.
Mentions: We next investigated how wild-type Aβ peptides interact with early-onset cerebral microvascular amyloid deposits comprised of CAA mutant Aβ in vivo. Biotin-labelled human wild-type Aβ40 or Aβ42 peptides were injected into the hippocampal region of twelve months old Tg-SwDI mice, a model that exhibits prominent cerebral microvascular amyloid deposition. The injected biotin-labelled human wild-type Aβ40 (Fig. 2a–c) or Aβ42 (Fig. 2d–f) peptides showed strong and preferential accumulation on pre-existing cerebral microvascular fibrillar amyloid deposits in the surrounding tissue. No accumulations were found when biotin alone was infused into similarly aged Tg-SwDI mice or when biotin-labelled wild-type Aβ peptides were infused into similarly aged wild-type mice without microvascular CAA (Supplementary Fig. 5). These results indicate that familial CAA mutant microvascular amyloid can serve as scaffold for rapid and robust co-deposition of wild-type Aβ peptides in brain.

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