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Researchers determine the structural basis for ApoE-Aβ interactions

MedicalXpress Breaking News-and-Events Dec 09, 2023

Alzheimer's disease (AD) is a debilitating incurable disease that affects millions of patients worldwide. Deposits of amyloid beta (Aβ) amyloid in the brain is key to AD pathology at early stages. Apolipoprotein E (apoE) interacts with Aβ and can influence this pathologic process. Although apoE-Aβ interactions have been extensively studied and have been proposed as a therapeutic target in AD, results of prior studies are confusing. Some report that apoE promotes Aβ amyloid formation while others report that apoE blocks this pathological process.

A new biophysical study from researchers at Boston University Chobanian & Avedisian School of Medicine explains why apoE and other apolipoproteins co-deposit with amyloids and provides a structural basis for understanding how apolipoproteins modulate amyloid growth and proliferation in the body.

"Our analysis of four different amyloid fibrils shows that apoE-amyloid interactions depend on the exact amyloid structure, termed polymorph. Amyloid polymorphs are disease- and tissue-specific and can differ in different experiments, which explains discrepancies among prior studies. Understanding such disease-specific factors is essential for harnessing apoE-Aβ interactions for therapeutic targeting," explains first author Emily Lewkowicz, a Ph.D. candidate in biophysics at the school.

The researchers used four different structures of Aβ fibrils from the brains of patients with Alzheimer's and other neurodegenerative diseases. To build models of apoE in complexes with different fibrils, they performed protein docking (the prediction of the structure of the complex based on the structures of the individual proteins) using computer modelling, followed by molecular dynamics simulations to test the stability of the complex.

The computational results, taken together with prior experimental data, revealed the driving forces and the molecular mechanisms for apolipoprotein binding to amyloid fibrils.

According to the researchers, apolipoproteins such as apoE are "amyloid signature proteins" that are found in amyloid deposits and probably influence their formation. "Our work shows how these proteins can interact directly with various amyloids and thereby promote or block their growth and proliferation by binding alongside fibrils or at their ends," adds corresponding author Olga Gursky, Ph.D., professor of pharmacology, physiology & biophysics at the school.

Besides Aβ, nearly 40 other proteins form pathologic amyloids in various human diseases, including Parkinson's disease, chronic traumatic encephalopathy, light chain amyloidosis, and many other life-threatening disorders. Apolipoproteins such as apoE are found in all these amyloid deposits. This work shows how these proteins can interact directly with amyloids and thereby influence their physical and biological properties.

These findings appear online in Cellular and Molecular Life Sciences.

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