Aβ-protein polymerization in Alzheimer disease: Optimal control for nucleation parameter estimation

Area of Science:

• Neuroscience
• Biophysics
• Mathematical Biology

Background:

• Alzheimer's disease is linked to the amyloid cascade hypothesis.
• Amyloid-beta (Aβ) protein oligomers are considered the primary pathogenic agents.
• The formation dynamics of Aβ oligomers involve Amyloid Precursor Protein (APP) cleavage and subsequent polymerization/nucleation.

Purpose of the Study:

• To model the formation dynamics of pathogenic Aβ oligomers.
• To propose an optimal control problem for estimating the nucleation rate.
• To investigate the role of nucleation in the amyloid cascade hypothesis.

Main Methods:

• Utilizing a Becker-Döring type model to describe Aβ formation dynamics.
• Developing an optimal control framework to estimate kinetic parameters.
• Focusing on the nucleation step, which lacks experimental measurement.

Main Results:

• A mathematical model simulating Aβ oligomer formation from monomeric Aβ.
• An optimal control problem formulation to estimate the nucleation rate.
• Identification of nucleation as a critical, yet unquantified, step in Alzheimer's pathogenesis.

Conclusions:

• The proposed optimal control method provides a novel approach to estimate the nucleation rate.
• Understanding and quantifying nucleation is crucial for validating the amyloid cascade hypothesis.
• This modeling approach offers insights into Alzheimer's disease mechanisms and potential therapeutic targets.