Two structurally defined Aβ polymorphs promote different pathological changes in susceptible mice

Misfolded Aβ is involved in the progression of Alzheimer's disease (AD). However, the role of its polymorphic variants or conformational strains in AD pathogenesis is not fully understood. Here, we study the seeding properties of two structurally defined synthetic misfolded Aβ strains (termed 2...

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Bibliographic Details
Published in:EMBO reports 2023-08, Vol.24 (8), p.e57003-n/a
Main Authors: Gomez‐Gutierrez, Ruben, Ghosh, Ujjayini, Yau, Wai‐Ming, Gamez, Nazaret, Do, Katherine, Kramm, Carlos, Shirani, Hamid, Vegas‐Gomez, Laura, Schulz, Jonathan, Moreno‐Gonzalez, Ines, Gutierrez, Antonia, Nilsson, K Peter R, Tycko, Robert, Soto, Claudio, Morales, Rodrigo
Format: Article
Language:English
Subjects:
Aggregates
Alzheimer Disease - genetics
Alzheimer Disease - metabolism
Alzheimer's disease
Amyloid beta-Peptides - metabolism
amyloid‐beta
Animal models
Animals
Biological properties
Fibrils
Inflammation
Mice
Mice, Transgenic
Molecular structure
Neurodegenerative diseases
Pathogenesis
Peptides
Plaque, Amyloid - metabolism
Plaque, Amyloid - pathology
prion
protein conformation
Protein seeding
Proteolysis
Seeds
strains
Transgenic animals
Transgenic mice
Tropism
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Summary:Misfolded Aβ is involved in the progression of Alzheimer's disease (AD). However, the role of its polymorphic variants or conformational strains in AD pathogenesis is not fully understood. Here, we study the seeding properties of two structurally defined synthetic misfolded Aβ strains (termed 2F and 3F) using in vitro and in vivo assays. We show that 2F and 3F strains differ in their biochemical properties, including resistance to proteolysis, binding to strain‐specific dyes, and in vitro seeding. Injection of these strains into a transgenic mouse model produces different pathological features, namely different rates of aggregation, formation of different plaque types, tropism to specific brain regions, differential recruitment of Aβ40/Aβ42 peptides, and induction of microglial and astroglial responses. Importantly, the aggregates induced by 2F and 3F are structurally different as determined by ssNMR. Our study analyzes the biological properties of purified Aβ polymorphs that have been characterized at the atomic resolution level and provides relevant information on the pathological significance of misfolded Aβ strains. Synopsis Two structurally defined Aβ conformational variants differ in their biochemical properties in vitro and induce different pathological features in a transgenic mouse model. Amyloid pathology induced by different Aβ strains is characterized by different tropism, morphology, and tinctorial properties. Synthetic Aβ fibrils (2F and 3F) preferentially seed Aβ40 while in vivo‐derived seeds have a preference to recruit Aβ42. Neuroinflammation induced in treated mice is Aβ strain specific. Seeded aggregates induced by structurally different Aβ strains in mice display different conformations. Two structurally defined Aβ conformational variants differ in their biochemical properties in vitro and induce different pathological features in a transgenic mouse model.
ISSN:1469-221X
1469-3178
1469-3178
DOI:10.15252/embr.202357003