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Professor Patrick Kehoe

Professor Patrick Kehoe

Professor Patrick Kehoe
B.Sc.(Dub.), Ph.D.(Wales)

Gestetner Professor of Translational Dementia Research

Area of research

Molecular Epidemiology and Translational Research into Dementia therapeutics

Institute of Clinical Neurosciences, Lev,
Learning and Research Building, Southmead Hospital BS10 5NB
(See a map)

+44 (0) 117 41 47800

Summary

As Gestetner Professor of Translational Dementia Research, I jointly head (with Professor Seth Love), the Dementia Research Group in Bristol Medical School: Translational Health Sciences, at the University of Bristol.

I gained a Joint Honours BSc in Pharmacology and Molecular Genetics from University College Dublin (Ireland) and my PhD on the Molecular Genetics of Alzheimer’s disease from Cardiff University (UK). I am currently a member of the Research Strategy Council for the UK Alzheimer’s Society, and a member of the Executive Committee of the European Alzheimer’s disease Consortium (EADC). To date I have contributed to over 170 publications.

My main research interest for well over a decade has investigated mechanisms that may underlie the widely acknowledged, but still poorly understood, association between hypertension and blood pressure regulation with respect to the development of Alzheimer’s disease (AD) and other dementias. Of particular interest is the role of the renin angiotensin system (RAS) in the pathology of AD and related neurodegenerative diseases, a topic of interest first started during my PhD work where I discovered variation in the ACE gene to be a risk factor for Alzheimer’s disease, which set me on my current research path.

Over the last 15 years, the work of my group and that from work with valuable colleagues in rewarding collaborations to investigate the role of RAS in AD has helped to unveil the prominence and importance of RAS in a number of pathological processes in AD. In doing so it provides some way of explaining the longheld recognition but limited understanding of associations between blood pressure regulation and dysfunction and the development and progression of dementia, particularly AD. The RAS is increasingly recognised for having interactions with many of the pathological pathways recognised in AD including interference with cerebral blood flow, inflammation, neurotransmitter imbalances as well as hypoxia and oxidative stress.  Our research has now informed the basis of a number of drug repurposing clinical trials of RAS-acting drugs in Alzheimer's disease, one of the largest of which, that I lead as Chief Investigator, is a multi-site clinical trial (RADAR) of a RAS-acting drug losartan in Alzheimer’s disease, that will complete in Summer 2019.

My other areas of interest include the aetiology of various forms of Vascular Cognitive Impairment (VCI). We are currently undertaking a large international collaborative project to try and identify genetic risk factors for VCI, potential synergies with genetic risk factors for stroke, but also to undertake research to harmonise the conceptualisation and classification of different forms of VCI.

The Dement ia Research Group has a multidisciplinary and applied approach to the investigation of the neuropathology of Alzheimer's disease and related dementia. This includes the use of genomic and various proteomic/metabolomic approaches further supported by additional molecular biological, cell culture in conjunction with histological and immunohistochemical approaches that are largely underpinned by tissue from the South West Dementia Brain Bank (SWDBB) or Brains for Dementia Research. Our focus is to ensure effective translation of pre-clinical research findings into meaningful outcomes such as the identification of new therapeutic targets to be tested in clinical trials, or biomarkers that may inform future research and/or clinical applications 

Activities / Findings

  • Role of Cerebral Amyloid Angiopathy in AD
  • Topographical mapping of components of the Renin Angiotensin Aldosterone System in AD and elderly non-demented brain tissue
  • The roles of Angiotensin Converting Enzyme 1 (ACE), Insulin Degrading Enzyme (IDE), Neprilysin (NEP) and Endothelin Converting Enzyme 1 (ECE-1) with respect to the levels of amyloid associated pathology in AD and CAA
  • Studies of TGF-beta, Low Density Lipoprotein Related Receptor Protein 1 (LRP-1), alpha2-macroglobulin receptor (A2M) and Receptor for Advance Glycation Products (RAGE) in A-beta clearance in CAA and AD brain
  • The role of lipids and lipid peroxidation in the pathogenesis of AD
  • Role of pro-inflammatory IL-10 and components of TNF-alpha signalling pathway with respect to genetic variation in AD risk and pathology
  • Role of extracellular matrix in AD pathogenesis
  • The relationship between NEP and severity of AD
  • Development of an in vitro model of the Extracellular Matrix
  • A study of oligomeric forms of A b in the pathology of AD and CAA
  • The role of ECE-1 and ECE-2 in the development of AD pathology
  • Relationship between genetic variation and pathology of known genetic candidates for AD

Keywords

  • Amyloid
  • Angiotensin
  • Clinical Trials
  • Dementia
  • Gene
  • Immunohistochemistry
  • Neuropathology
  • Pharmacoepidemiology
  • Tau

Skills

  • Alzheimer's disease
  • Cerebral Amyloid Angiopathy
  • Dementia
  • Hypertension
  • Vascular Cognitive Impairment
  • Vascular Dementia

Processes and functions

  • Memory and cognitive function
  • Gene variation
  • Enzyme activity

Methodologies

  • Sequencing
  • PCR
  • Western Blotting
  • Immunohistochemistry (formalin fixed and frozen)
  • Genotyping (enzyme and Taqman)
  • Microscopy
  • Zymography
  • HPLC
  • semi-automated immunohistochemistry quantification
  • Cell Culture
  • ELISA and immunohistochemical activity assays

Expertise

15 years of working in dementia. Discovered that angiotensin converting enzyme gene (ACE) variation was a risk factor for Alzheimer?s disease (AD) which has prompted a number of investigations by us and others showing that angiotensins are involved in AD. Worked on one of the largest ever genetic linkage studies conducted in AD patients. Have championed that given certain laboratory based findings there may be sufficient data to prompt further work needing to be done and stronger consideration to be made on the potential adverse consequences of prescribing certain types of anti-hypertensive medications to people given possible adverse risks for dementia. Was a lead member of recent efforts to achieve an international consensus for the post-mortem assessment of cerebral amyloid angiopathy. Expertise now refined to roles of genes and protein activity on development, pathology and progression of AD.

  • Alzheimer's disease
  • genes
  • blood pressure and dementia
  • hypertension and dementia
  • cognitive decline
  • degrading enzymes
  • angiotensin
  • Recent publications

    View complete publications list in the University of Bristol publications system

    Networks & contacts

    • Various members from a number of Alzheimer’s Research UK Network Centres
    • Members of the European Alzheimer's Disease Consortium (EADC)

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