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Intracerebroventricular Injection of Amyloid-β Peptides in Normal Mice to Acutely Induce Alzheimer-like Cognitive Deficits
Published on: March 16, 2016
Two structurally defined Aβ polymorphs promote different pathological changes in susceptible mice
Ruben Gomez-Gutierrez1,2, Ujjayini Ghosh3, Wai-Ming Yau3
1Department of Neurology, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Abstract:
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.
Insights
Different strains of misfolded amyloid-beta (Aβ) show distinct properties and induce unique pathologies in Alzheimer's disease models. Understanding these Aβ strains is crucial for disease mechanism insights.
Area of Science:
- Neuroscience
- Biochemistry
- Pathology
Background:
- Misfolded amyloid-beta (Aβ) aggregates are implicated in Alzheimer's disease (AD) progression.
- The specific roles of Aβ polymorphic variants and conformational strains in AD pathogenesis remain incompletely understood.
Purpose of the Study:
- To investigate the seeding properties and biological impact of two structurally defined synthetic misfolded Aβ strains (2F and 3F).
- To elucidate how different Aβ strains contribute to AD pathology.
Main Methods:
- In vitro biochemical assays assessing proteolysis resistance, dye binding, and seeding.
- In vivo studies involving injection into a transgenic mouse model of AD.
- Solid-state nuclear magnetic resonance (ssNMR) for structural analysis of induced aggregates.
Main Results:
- The 2F and 3F Aβ strains exhibited distinct biochemical properties and in vitro seeding behaviors.
- In vivo, these strains induced varying aggregation rates, plaque morphologies, brain region tropism, and Aβ peptide recruitment (Aβ40/Aβ42).
- Differential microglial and astroglial responses were observed, and ssNMR confirmed distinct structures of induced aggregates.
Conclusions:
- Structurally distinct Aβ polymorphs possess unique biological activities and pathological consequences.
- This research provides atomic-level characterization of Aβ polymorphs, offering critical insights into their pathological significance in Alzheimer's disease.
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