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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
Pyroglutamate amyloid β (Aβ) aggravates behavioral deficits in transgenic amyloid mouse model for Alzheimer disease
Jessica L Wittnam1, Erik Portelius, Henrik Zetterberg
1Division of Molecular Psychiatry, Georg August University Göttingen, University Medicine Göttingen, 37075 Göttingen, Germany.
Abstract:
Pyroglutamate-modified Aβ peptides at amino acid position three (Aβ(pE3-42)) are gaining considerable attention as potential key players in the pathogenesis of Alzheimer disease (AD). Aβ(pE3-42) is abundant in AD brain and has a high aggregation propensity, stability and cellular toxicity. The aim of the present work was to study the direct effect of elevated Aβ(pE3-42) levels on ongoing AD pathology using transgenic mouse models. To this end, we generated a novel mouse model (TBA42) that produces Aβ(pE3-42). TBA42 mice showed age-dependent behavioral deficits and Aβ(pE3-42) accumulation. The Aβ profile of an established AD mouse model, 5XFAD, was characterized using immunoprecipitation followed by mass spectrometry. Brains from 5XFAD mice demonstrated a heterogeneous mixture of full-length, N-terminal truncated, and modified Aβ peptides: Aβ(1-42), Aβ(1-40), Aβ(pE3-40), Aβ(pE3-42), Aβ(3-42), Aβ(4-42), and Aβ(5-42). 5XFAD and TBA42 mice were then crossed to generate transgenic FAD42 mice. At 6 months of age, FAD42 mice showed an aggravated behavioral phenotype compared with single transgenic 5XFAD or TBA42 mice. ELISA and plaque load measurements revealed that Aβ(pE3) levels were elevated in FAD42 mice. No change in Aβ(x)(-42) or other Aβ isoforms was discovered by ELISA and mass spectrometry. These observations argue for a seeding effect of Aβ(pE-42) in FAD42 mice.
Insights
Pyroglutamate-modified amyloid-beta (Aβ(pE3-42)) peptides accelerate Alzheimer disease (AD) pathology. New mouse models show that elevated Aβ(pE3-42) worsens AD symptoms and pathology, suggesting a key role in disease progression.
Area of Science:
- Neuroscience
- Biochemistry
- Genetics
Background:
- Pyroglutamate-modified amyloid-beta (Aβ(pE3-42)) peptides are implicated in Alzheimer disease (AD) pathogenesis.
- Aβ(pE3-42) is abundant in AD brains and exhibits high aggregation propensity, stability, and toxicity.
Purpose of the Study:
- To investigate the direct impact of elevated Aβ(pE3-42) levels on existing AD pathology.
- To characterize the Aβ peptide profile in established and novel transgenic mouse models.
Main Methods:
- Generation of a novel transgenic mouse model (TBA42) expressing Aβ(pE3-42).
- Characterization of Aβ peptide profiles in 5XFAD and TBA42 mice using immunoprecipitation and mass spectrometry.
- Cross-breeding of 5XFAD and TBA42 mice to create FAD42 mice and assessment of their phenotype, Aβ levels, and plaque load.
Main Results:
- TBA42 mice exhibited age-dependent behavioral deficits and Aβ(pE3-42) accumulation.
- 5XFAD mouse brains contained a mix of Aβ isoforms, including Aβ(pE3-42).
- FAD42 mice displayed aggravated behavioral phenotypes and elevated Aβ(pE3) levels compared to single transgenic models, without changes in other Aβ isoforms.
Conclusions:
- Elevated Aβ(pE3-42) exacerbates Alzheimer disease pathology and behavioral deficits.
- Aβ(pE3-42) appears to act as a seeding factor, driving the progression of AD pathology.
- These findings highlight Aβ(pE3-42) as a critical therapeutic target for Alzheimer disease.
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