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Professor Patrick Kehoe

Professor Patrick Kehoe

Professor Patrick Kehoe
BSc(Dub), PhD(Wales)

Gestetner Professor of Translational Dementia Research

Area of research

Molecular Epidemiology and Translational Research into Dementia therapeutics

Clinical Neurosciences,
University of Bristol, Level 1 Learning and Research Building BS10 5NB
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+44 (0) 117 41 47800

Summary

Together with Professor Seth Love, I jointly head the Dementia Research Group, a part of the Institute of Clinical Neurosciences, and the School of Clinical Sciences

My main research interest for 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. This increasingly appears to be multifunctional in its associations with many of the pathological pathways recognised in AD including cerebral blood flow reductions, inflammation, neurotransmitter imbalances and oxidative stress. We are currently leading on a multi-site clinical trial (RADAR) of a RAS-acting drug losartan in Alzheimer’s disease. This is based on earlier work we have undertaken on the RAS has also served as a template for other investigations into the behaviour and involvement in AD and other dementias of other related vasomodulatory enzymes such neprilysin, insulin-degrading enzyme and endothelin-converting enzymes.

My other areas of interest include the aetiology of various forms of Vascular Cognitive Impairment (VCI). We undertake research 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 Dementia Research Group has a multidisciplinary and applied approach to the investigation of the neuropathology of Alzheimer's disease. 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.

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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