A Novel Way of Removing Toxic Material from the Brain in Early Alzheimer’s Disease

Matthew Campbell, PhD
Trinity College Dublin (Dublin, Ireland)

Co-Principal Investigators

Peter Humphries, PhD
Trinity College Dublin (Dublin, Ireland)
Year Awarded:
2015
Grant Duration:
July 1, 2015 to June 30, 2019
Disease:
Alzheimer's Disease
Award Amount:
$250,000
Grant Reference ID:
A2015548S
Award Type:
Standard
Award Region:
International
Matthew Campbell, PhD

Novel Amyloid-beta Clearance Mechanisms at the Blood-Brain Barrier

Summary

Alzheimer’s disease (AD) is characterized by accumulation of a small peptide, amyloid-beta, in the brain and a major factor in this build-up appears to be impaired clearance of amyloid-beta in AD of sporadic onset (i.e., non-familial forms). Positioned along the cerebral blood vessels, the blood-brain barrier (BBB) functions as a tightly regulated site of macromolecule exchange between the brain tissue and circulation. Previous work has identified transcellular receptors of amyloid-beta at the BBB. We have shown that paracellular tight junction protein complexes linking brain endothelial cells together are altered in AD, and that clearance of amyloid-beta is increased following modulation of targeted tight junction proteins. We propose to examine the role of novel tight junction proteins in AD and assess whether tight junction protein modulation in combination with monoclonal antibodies targeting amyloid-beta could act as a novel therapeutic strategy.

Details

The primary goal of this research project is to develop a greater understanding of the integrity of blood vessels in the brain in the context of Alzheimer's disease.  In addition, we hope to develop a novel form of therapy aimed at removing the toxic amyloid-beta peptide from the brains of individuals with Alzheimer's disease.

The brain is an energy-demanding tissue requiring nutriment and oxygen, while at the same time needing protection from other potentially harmful agents, for example, viral or bacterial particles which may be delivered by the circulation.  For this reason, cells lining the walls of the fine capillaries that supply blood to the brain have tight junctions, which, as the name implies, reduce the space between these cells essentially to zero, forming an exceedingly tight seal.  This barrier is termed the blood-brain barrier (BBB) and it performs the essential role of preventing the majority of blood-borne components from gaining access to delicate neural tissues.  Here, we will examine how amyloid beta, a peptide that has previously been found to accumulate in the brains of Alzheimer's disease patients, can exert an impact on the tight junctions and how we may be able to facilitate greater clearance of amyloid-beta from brain blood using a technology termed RNA-interference combined with current antibody-based developmental drugs.

We believe our project focuses on an area of Alzheimer's disease pathology that has remained largely unexplored to date.  In addition, the findings associated with this project have the potential to lead to a novel form of combination therapy for Alzheimer's disease that could offer hope to patients and carers alike.

Once this study is completed, we hope to be in a position where we will have a more profound understanding of the "dysfunctional" BBB in Alzheimer's disease.  Added to this, we envision the development of a new form of therapy that could have multiple benefits in the clinical management of Alzheimer's disease.

About the Researcher

Dr. Matthew Campbell, PhD, is a research assistant professor and lecturer in genetics at the Smurfit Institute of Genetics at Trinity College Dublin (TCD), Ireland.  He leads the Neurovascular Genetics Research group at the same institution.  Dr. Campbell graduated from University College Dublin (UCD) in 2006 with a PhD in Biochemistry, then focused on the role of tight junctions in the development of degenerative eye conditions. In the same year, he joined the Genetics Department in TCD and focused primarily on the molecular biology and physiology of the vasculature associated with neural tissues, including the brain and retina. He has published extensively on the use of RNA interference (RNAi) to modulate levels of distinct tight junction proteins at the BBB/inner blood retina barrier (BBB/iBRB) in vivo.



"Almost everyone knows somebody who has been affected by Alzheimer’s.  In my case it was my great-aunt Helen, whose daughter Claire called it ‘a very lonely illness for both the patient and their carers.’  At my request, Claire recounted some of the challenges she faced during her mother's illness. They included a lack of information and support, and a stigma attached to Alzheimer which made dealing with it much worse.

My mother, who had reared me in a most wonderful loving home, was now in need of my care and attention.  I was given no real tangible information except that her medical condition would deteriorate. Myself and my wonderful husband and children were the only real day-to-day support my mother had. As the illness progressed and her physical health became more frail and her speech very limited, there was still no information. We just muddled along.

Claire and her family never had an opportunity to learn about research into AD, including clinical trials and the hope of drug development.  Through ADR grants, and its efforts to publicize promising research on its website, BrightFocus offers hope to millions of families like Claire’s who are alone and coping with the burden of this disease."

Publications

Doherty CP, O'Keefe E, Wallace E, Loftus T, Keaney J, Kealy J, Humphries MM, Molloy MG, Meaney JF, Farrell M, Campbell M. Blood-Brain Barrier Dysfunction as a Hallmark Pathology in Chronic Traumatic Encephalopathy. J Neuropathol Exp Neurol. 2016 May 31. pii: nlw036. [Epub ahead of print] PubMed Icon Google Scholar Icon

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