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The A2V mutation as a new tool for hindering Aβ aggregation: A neutron and x-ray diffraction study
Laura Cantu'1, Laura Colombo2, Tatiana Stoilova2
1Department of Medical Biotechnology and Translational Medicine, University of Milan, LITA, Segrate, 20090, Milano, Italy.
Scientific Reports
|July 16, 2017
Summary
A novel APP gene mutation (A673V) causes early-onset Alzheimer's disease (AD) in homozygous individuals but protects heterozygotes. This A673V mutation alters amyloid-beta (Aβ) aggregation and fibril structure.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) plaque formation.
- Genetic mutations in the amyloid precursor protein (APP) gene are linked to familial forms of AD.
- The A673V mutation in the APP gene presents a unique dichotomy, causing early-onset AD in homozygotes and offering protection in heterozygotes.
Purpose of the Study:
- To investigate the structural and aggregation properties of the amyloid-beta (Aβ) peptide with the A673V mutation.
- To understand how the A673V mutation influences Aβ fibril formation and assembly.
- To elucidate the role of the Aβ N-terminal domain in amyloid fibril formation in the context of the A673V mutation.
Main Methods:
- Neutron diffraction (ND) and X-ray diffraction (XRD) experiments were performed on magnetically-oriented fibers of wild-type Aβ1-28 (Aβ1-28WT) and its A673V variant (Aβ1-28A2V).
- Comparative analysis of diffraction patterns to determine differences in fibril structure and lateral packing.
- Assessment of orientation propensity and aggregation behavior of single peptides and their mixtures, including a short N-terminal fragment (Aβ1-6A2V).
Main Results:
- The Aβ1-28A2V variant exhibited higher orientation propensity, indicating enhanced fibril formation.
- Distinct diffraction patterns between Aβ1-28WT and Aβ1-28A2V assemblies revealed differences in lateral packing of Aβ peptides.
- Mixtures of Aβ peptides showed structural interference, with the lowest orientation propensity observed for Aβ1-28WT mixed with Aβ1-6A2V, highlighting the N-terminal domain's role.
Conclusions:
- The A673V mutation significantly alters Aβ aggregation properties and fibril structure.
- The differential effects of the A673V mutation in homozygous and heterozygous states are linked to its impact on Aβ assembly.
- The N-terminal domain of Aβ plays a crucial role in amyloid fibril formation, as evidenced by the A673V mutation studies.
