Characterization of Waste Clearance Pathways in the Vertebrate Brain

Benjamin Hogan, PhD
University of Melbourne (Melbourne, Victoria Australia)

Co-Principal Investigators

Neil Bower, PhD
The University of Queensland (Brisbane, Queensland, Australia)

Collaborators

Jana Vukovic, PhD
The University of Queensland (Brisbane, Queensland, Australia)
Robert Parton, PhD
The University of Queensland (Brisbane, Queensland, Australia)
Joseph Powell, PhD
The University of Queensland (Brisbane, Queensland, Australia)
Year Awarded:
2018
Grant Duration:
July 1, 2018 to June 30, 2021
Disease:
Alzheimer's Disease
Award Amount:
$295,439
Grant Reference ID:
A2018807S
Award Type:
Standard
Award Region:
International
Benjamin Hogan, PhD

Characterization of a Newly Described Scavenger Cell Type in the Meningeal Vasculature

Summary

Normal function of the brain vasculature and the clearance of harmful wastes from the brain are central in the progression of Alzheimer's disease. This project focuses on understanding a cell type that surrounds blood vessels in the brain and actively clears potentially harmful debris and waste. We will determine the role played by this cell type in clearance of wastes in aging brains and the potential role of this cell type in neurodegeneration. We aim to develop a new understanding of how the brain is cleaned, with a hope that manipulating these processes in the future might provide a new strategy to fight disease progression.

Details

Normal function of the brain vasculature and the clearance of harmful wastes from the brain are central in the progression of Alzheimer's disease. Yet there is much that we do not yet understand about the control of neurovascular function and its role in the clearance of wastes. We have recently identified and described a type of cell that actively scavenges waste and surrounds blood vessels in the meninges, the outer layers surrounding the vertebrate brain. We made this discovery by examining the developing neurovasculature of larval zebrafish with powerful, live-imaging approaches. This project focuses on understanding and manipulating this newly appreciated cell type in the brains of fish and mammals to explore its potential roles in clearance of wastes.

We will carefully determine the role played by this cell type in clearance of waste in aging brains and the potential role of this cell type in neurodegeneration. For this we will use genetic models that lack this cell type. We will apply cutting edge genomic methodologies with single cell resolution to understand how these cells influence the brain. We will also develop three-dimensional electron microscopy maps of brains to observe cellular changes controlled by these scavenger cells in meninges. We will examine the equivalent cell types in mice with cellular resolution genomics and develop new ways to manipulate their functions in disease settings.

This project aims to develop a new understanding of how the brain is cleaned, with the hope that in the future, it might be possible to manipulate these central mechanisms as a new strategy to fight disease progression.

About the Researcher

This project is jointly led by Associate Professor Ben Hogan and Dr Neil Bower from the Institute for Molecular Bioscience, a leading life sciences institute at the University of Queensland, Australia.

Ben Hogan received his PhD from Melbourne University in 2005, and following postdoctoral studies in the Netherlands, founded his laboratory in 2010, to study the molecular genetic control of vascular development. Neil Bower received his PhD from the University of Queensland in 2006. He has worked as a post-doctoral researcher at the University of St Andrews, Scotland, examining growth factor signaling in muscle development in salmon and mice. In 2011, Neil joined the Hogan laboratory and has since been pioneering studies of the zebrafish brain vasculature. Together Hogan and Bower recently described scavenger cells that modulate meningeal angiogenesis and clear waste from the brain and blood vessels.  This work was published in Nature Neuroscience and provides the basis for the ongoing research funded by Brightfocus. This project has been a catalyst for new research questions in the Hogan laboratory, shifting significant focus into understanding the blood brain barrier and neurovasculature in development and disease.

Personal Story

Ben Hogan grew up in a small country town in rural Australia. He was determined to go to university and find a career that might make a positive difference for people’s quality of life. In university it became obvious that science was a passion that might one day provide that opportunity. The idea of making a single fundamental breakthrough that changes lives, even if once in a career, has always been his driving motivation.

For many years the Hogan lab has been driven to investigate the molecular control of new vessel formation – a process that underpins many aspects of disease. Yet it is only recently that we have started to look into the vasculature of the brain. This has triggered our own growing appreciation for how important it is to first understand and then develop ways to manipulate formation of neurovasculature. We have been inspired by our recent observations to the idea that the vasculature and cells surrounding our brain vessels might offer real opportunities to manipulate the aging brain in settings of disease, including Alzheimer’s disease. The possibilities are vast and the potential to change lives is exciting.

Neil Bower comes from a family with a history of dementia and Alzheimer’s, and he has a strong personal interest and passion to understand how these neurological diseases progress.  The recent scientific discoveries from our lab and many other groups are expanding our understanding of how waste products are removed from the brain. Neil believes that we are on the verge of making considerable breakthroughs in the treatment and prevention of these diseases. 

With the funding provided by BrightFocus through the generosity of their donors, Neil and Ben are determined to further our understanding of the processes that control neurovascular function and clear wastes in the brain. By analyzing the development and functions of a novel cell type we have recently found, that clears waste in the brain, we hope take key steps towards future therapeutic approaches.

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