Therapeutic Effect of rApoA-I-Milano in an AD Model

Beta-amyloid (Aβ) protein accumulates abnormally in the Alzheimer’s brain, to a degree that is believed to be sufficient to induce neuronal cell death. Evidence suggests that the levels and distribution of lipids in the brain influence the transport and deposition of Aβ protein. The aim of this proposal is to determine the effect of a new treatment based on the administration of a natural modified protein that is able to mobilize lipids in a transgenic mouse model of AD. This protein, the ApoA-I-Milano variant, has been shown to be protective in cardiovascular diseases; however, its properties have never been tested in brain diseases.

My laboratory is studying the impact of recombinant ApoA-I-Milano protein on a cell culture model that mimics the environment of blood vessels in the human brain. First, we aim to determine whether the treatment influences the transport of cholesterol in the brain and how this mechanism might enhance the clearance of Aβ from brain to bloodstream. Second, we propose to test the effect of chronic or acute treatment with ApoA-I-Milano in a transgenic mouse model of AD. We will explore whether the intravenous administration of the recombinant protein is able to reduce Aβ accumulation in the mouse brain and prevent the cognitive and behavioral deficits associated with that pathology. If our hypothesis is confirmed, the results would support the idea that brain lipid metabolism is a crucial player in AD and that it can be therapeutically modified by a peripheral intervention.

In summary, in a pre-clinical model of AD, we propose to test a feasible treatment which is based on the modification of a compound that has previously shown positive results in patients with acute coronary syndrome. We believe that our project will underscore novel molecular insights related to the association between the cholesterol metabolism and Aβ accumulation in the brain.