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.
About the Researcher
Dr. Mar Hernández-Guillamon has dedicated her career to the study of Aβ-associated pathologies, including AD and cerebral amyloid angiopathy. This career direction started in 2000 during her PhD studies in the Biochemistry Department of the Neuroscience Institute, Universitat Autónoma de Barcelona, Spain. During her postdoctoral fellowship in the Neurovascular Research Lab of Vall d’Hebron Research Institute, Barcelona, she consolidated her experience in the neuroscience field and established her knowledge in clinical neurology. Part of her postdoctoral training was at the Pathology Department of the New York University (Langone Medical Center, New York City), where she studied the involvement of cellular proteases in the degradation of Aβ peptides. In 2012, she was awarded the Miguel Servet grant from the Spanish government to start her own research group, which is the Cerebral Amyloid Angiopathy laboratory at the Vall d’Hebron Research Institute, Barcelona.
My research has always been focused on how the health of the vascular system has a direct impact on certain neuropathologies. In particular, during the predoctoral and postdoctoral periods, I studied the molecular mechanisms involved in the neurovascular disorder known as cerebral amyloid angiopathy (CAA). CAA is characterized by Aβ deposition in the blood vessels of the brain. Currently, as a principal investigator, because of the overlap of CAA and AD, I have used my background knowledge of the cerebrovasculature system to study new therapeutic strategies for AD. We believe that we can help prevent Aβ deposition in the brain by influencing lipid metabolism and cholesterol transport.
Our proposal represents the kind of research I am interested in, which seeks to modify natural protein variants to be used as therapeutic options for human brain diseases. Being awarded this grant will allow me and my team to test and hopefully prove the hypothesis, which will take us a step closer to a novel treatment for AD. As a junior researcher, being given this opportunity by the BrightFocus Foundation will be of enormous help towards developing my scientific career and making our findings known throughout our institution and in the wider AD research community.
First published on: July 7, 2017
Last modified on: June 30, 2020