The impact of novel treatments on A\03B2 burden in Alzheimer's Disease: insights from a mathematical model
Year: 2011
Type: report
Abstract: Motivated by recent therapeutic initiatives for Alzheimer's disease, we developed a mathematical model of the accumulation of amyloid /3-protein (A/i) in the brain.The model incorporates the production and clearance of kl5 monomers, and the elongation and fragmentation of polymers by monomer aggregation and break-off, respectively.Our analysis suggests that A/3 dynamics are dictated by a single tmitless measure re- ferred to as the polymerization ratio, which is the product of the production and elongation rates divided by the product of the clearance and fragmentation rates.Cerebral k(i burden attains a finite steady-state level if this ratio is less than one, and undergoes sustained growth if this ratio is greater than one.The highly nonlinear relationship be- tween the polymerization ratio and the steady-state A/3 burden implies that a modest reduction in the polymerization ratio (e.g., a 40% reduction in the production rate by a 7-secretase inhibitor) achieves a significant (e.g., 18-fold) decrease in the A/3 burden.Our model also predicts that after initiation or discontinuation of treatment, it may take months to reach a new steady-state A/3 burden.Taken together, our findings suggest that the research comnumity should focus on developing agents that provide a modest reduction of the polymerization ratio while avoiding long-term toxicity.Fi- nally, our model can be used to indirectly estimate several crucial parameters that are difficult to measure directly: the production rate, the fragmentation rate and the strength (i.e., percentage inhibition or enhancement) of treatment.
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1578657576