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Genetic evidence for serum amyloid P component as a drug target in neurodegenerative disorders

Schmidt, A Floriaan; Finan, Chris; Chopade, Sandesh; Ellmerich, Stephan; Rossor, Martin N; Hingorani, Aroon D; Pepys, Mark B; (2024) Genetic evidence for serum amyloid P component as a drug target in neurodegenerative disorders. Open Biology , 14 (7) , Article 230419. 10.1098/rsob.230419. Green open access

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Abstract

The mechanisms responsible for neuronal death causing cognitive loss in Alzheimer's disease (AD) and many other dementias are not known. Serum amyloid P component (SAP) is a constitutive plasma protein, which is cytotoxic for cerebral neurones and also promotes formation and persistence of cerebral Aβ amyloid and neurofibrillary tangles. Circulating SAP, which is produced exclusively by the liver, is normally almost completely excluded from the brain. Conditions increasing brain exposure to SAP increase dementia risk, consistent with a causative role in neurodegeneration. Furthermore, neocortex content of SAP is strongly and independently associated with dementia at death. Here, seeking genomic evidence for a causal link of SAP with neurodegeneration, we meta-analysed three genome-wide association studies of 44 288 participants, then conducted cis-Mendelian randomization assessment of associations with neurodegenerative diseases. Higher genetically instrumented plasma SAP concentrations were associated with AD (odds ratio 1.07, 95% confidence interval (CI) 1.02; 1.11, p = 1.8 × 10 -3), Lewy body dementia (odds ratio 1.37, 95%CI 1.19; 1.59, p = 1.5 × 10 -5) and plasma tau concentration (0.06 log 2 (ng l -1) 95%CI 0.03; 0.08, p = 4.55 × 10 -6). These genetic findings are consistent with neuropathogenicity of SAP. Depletion of SAP from the blood and the brain, by the safe, well tolerated, experimental drug miridesap may thus be neuroprotective.

Type: Article
Title: Genetic evidence for serum amyloid P component as a drug target in neurodegenerative disorders
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1098/rsob.230419
Publisher version: https://doi.org/10.1098/rsob.230419
Language: English
Additional information: Copyright © 2024 The Authors. Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited.
Keywords: Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Alzheimer's disease, genome-wide association study, Lewy body dementia, miridesap, serum amyloid P component, C-reactive protein, C-REACTIVE PROTEIN, MENDELIAN RANDOMIZATION, PHARMACOLOGICAL DEPLETION, IN-VITRO, DISEASE, BRAIN, BETA, VARIANTS, BIAS, METAANALYSIS
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Population Science and Experimental Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/10209674
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