# Structural characterization of A-beta strain variation in AD mouse models

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2020 · $69,722

## Abstract

Abstract
Structurally dissimilar aggregates (strains) of the amyloid beta peptide (Aβ) in Alzheimer's Disease (AD) can
potentially explain differences seen in the progression and severity of the disease. Fibrils formed by synthetic
Aβ in vitro and Aβ fibrils seeded from patient brain extracts led to a variety of Aβ strains. Previous research with
AD brain seeded material led to Aβ structures that varied with patients and with the stage of disease, suggesting
that specific Aβ strains not only could affect the progression of AD but also potential treatment. However, a
bias using patient seeded synthetic Aβ is that seeding might select for those Aβ strains with the highest seeding
potential masking other strains that could be important in the disease. Our long-term goal is to understand
the basis of strain variation for several pathological proteins important in neurodegenerative disease such as
tau, α-synuclein, huntingtin, and Aβ. The objective of this application is to determine the in vivo-generated
structures of Aβ strains found within and between individual amyloid mouse models, which will answer the
following questions: 1) Are Aβ plaques found in individual mice composed predominantly of one strain or
mixtures of strains? Do strains depend on gender, brain region, or mouse model examined? How are strains
impacted by seeding mice with fibrils from human brains? 2) Are seeding experiments capturing the structural
variety found in AD brains or are they biased towards the most seeding competent species? 3) what are the
structural differences between these strains? We will address these questions in the following 3 specific aims:
In Aim 1, we will directly detect the Aβ strain variety and distribution in mouse models of amyloid pathology.
This will be accomplished by measuring solid-state NMR spectra on brain extracts purified from 15N labeled
APPKINL-F, APPKINL-G-F, and 5XFAD mice. A subset of 5XFAD mice will be seeded with AD patient brain extract.
In Aim 2, we will determine the seeding potential of Aβ strains from amyloid mouse models. We will seed
recombinant Aβ with brain extract from amyloid pathology mouse models, measure the seeding kinetics of
different strains, and compare their NMR spectra to those of the original mouse brain extract and those of Aβ
seeded from human AD brain extract. In Aim 3 we will determine the structures of a basis set of Aβ strains from
amyloid mouse models. We will use an innovative solid-state NMR and EPR approach to determine high-
resolution structures of Aβ that capture short and long-range order details. The expected outcome of these
aims is that we will pioneer NMR spectroscopy on vivo-generated Aβ aggregates. We will map the distribution
of Aβ strains throughout the brain, and determine the dependence of strains on brain region, gender, age, and
mouse model. We will correlate the NMR structures with brain pathology by histology and biochemistry. We
will develop a combined EPR and solid-state NMR approach ...

## Key facts

- **NIH application ID:** 10143818
- **Project number:** 3R01AG061865-03S1
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Ralf Langen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $69,722
- **Award type:** 3
- **Project period:** 2018-09-30 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10143818

## Citation

> US National Institutes of Health, RePORTER application 10143818, Structural characterization of A-beta strain variation in AD mouse models (3R01AG061865-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10143818. Licensed CC0.

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