Plasma Protein-mediated Effects of ApoE4 Expression on Brain in AD
Possession of the APOE-ε4 gene confers a strong risk for earlier onset of Alzheimer’s disease (AD), a devastating brain disorder that damages brain synapses, or connections between neurons, and ultimately the neurons themselves that are responsible for memory and learning, as well as executive function. While it is clear that AD creates widespread damage within the brain itself, it is unclear whether the upstream cause of the disease may lie in changes that occur in the blood, ultimately influencing brain health. Support for this hypothesis can be found in the context of normal aging in which blood factors from old individuals drive characteristics of aging. This proposal will directly investigate how manipulating proteins in the blood influences the impact that the risk-conferring APOE-ε4 gene has on Alzheimer’s disease and the extent to which APOE- ε4’s harmful effects can be rescued with more neutral forms of the gene. The results possibly will provide fresh insights into new treatment avenues.
The overall goal of this project is to clarify the role of blood-borne proteins in the Alzheimer's risk conferred by expression of the APOE4 gene. While it is clear that APOE4 expression drives pathological changes within the brain itself, it is unclear whether the upstream cause of this damage may lie in changes that occur in the blood, a hypothesis we will directly assess in the first aim using next-generation protein profiling in both human blood samples and in blood isolated from mouse models of human APOE expression. We will directly address whether changes in the blood that occur as a result of APOE4 expression can drive changes in brain function and whether they influence hallmark Alzheimer's pathology. We will also pursue the identification of putative protective factors present within APOE3-expressing mice that may be used to target or revert APOE4-induced dysfunction in affected individuals, which we hope will inform the creation of novel therapeutic strategies.
Despite knowing that APOE4 is the strongest genetic risk factor for AD, the molecular details underlying its strong association with AD, and how it affects the brain either independently or through canonical Alzheimer's pathology, have remained unclear. This proposal will test the concept that APOE4 alters molecules in the blood in a manner that alters brain function, ultimately exacerbating the brain’s response to Alzheimer’s pathogenesis. This new area of APOE4 inquiry will yield new insights into how the peripheral compartment acts to shape the brain’s response to disease, while provide clues to how other immune-related risk factors may play a role in the disease process. The insights gained from this novel direction may provide a simplified therapeutic approach to treating Alzheimer's patients that targets molecules in the blood.
About the Researcher
As a graduate student, Dr. Castellano studied how the strongest genetic risk factor for Alzheimer's disease (AD) influences metabolism of the pathogenic peptide, amyloid beta, within brain interstitial fluid. In David Holtzman’s group, he used in vivo microdialysis to show in behaving mice that clearance of this peptide is impeded by the presence of APOE4, whereas clearance in the context of more inert or protective forms is faster. As he transitioned into postdoctoral training, Dr. Castellano became fascinated by the possibility that brain function may be, in part, shaped by the immune system and by unexplored activities present within circulation. In postdoctoral work with Tony Wyss-Coray, PhD, Dr. Castellano sought to identify and characterize factors in the periphery that reverse features of brain aging, using parabiosis and plasma transfer to demonstrate features of blood-borne brain revitalization. He pioneered the use of an immunodeficient mouse model to show that systemic treatment with human umbilical cord plasma revitalizes hippocampal function in aged mice. He went on to identify TIMP2 as a critical pro-plasticity protein within young blood that recapitulates many of the previously reported rejuvenation phenotypes, which uncovered many research directions into the basic function of TIMP2 within the hippocampus. The Castellano laboratory now focuses on characterizing the activity of TIMP2 and its action in mediating long-range effects on circuits in the brain in the context of AD and other disorders.
Growing up, I was fascinated by the outdoors and could often be found collecting specimens of anything and everything that would fit under my small microscope. This curiosity followed me to college, where I majored in biochemistry and molecular biology. I loved both the precision and exactness that could be found in areas of chemistry, and the complexity and murkiness of the unknown that could be found in biology. I volunteered in a laboratory run by Phyllis Robinson, PhD, who studies the biophysical and signaling properties of various opsins. She imbued in me a determination to address only the most interesting questions -- in her view, testing and solving life's riddles was more than half the fun. My grandfather suffered with Alzheimer's disease when I was in high school, and I felt compelled to combine my interest in the basic mechanisms underlying memory with the unmet need to address the Alzheimer's epidemic. My curiosity and drive to answer questions related to Alzheimer's and aging was nurtured as a graduate student in Dave Holtzman's laboratory where I began a longstanding interest in studying the association between APOE4 and Alzheimer's risk. I expanded my understanding and perspective by working as a postdoc in Tony Wyss-Coray's group, where I pursued the novel direction of altering brain aging by using molecules in the blood. I am incredibly grateful for the support provided by BrightFocus donors for allowing me to combine the insights I gained in aging research with my longstanding interest in APOE biology. This project represents a fresh approach that promises to generate novel insights into putative mechanisms underlying the strong association of APOE4 and Alzheimer's disease risk.
First published on: June 26, 2018
Last modified on: July 3, 2018