ASC specks as a single-molecule fluid biomarker of inflammation in neurodegenerative diseases
Immunotherapeutic strategies for Alzheimer's and Parkinson's disease would be facilitated by better measures of inflammation. Here we established an ultra-sensitive single-molecule pull-down immunoassay combined with direct stochastic optical reconstruction microscopy (dSTORM) to measure the number, size and shape of individual extracellular inflammasome ASC specks. We assayed human post-mortem brain, serum and cerebrospinal fluid of patients with Parkinson's and Alzheimer's as well as healthy elderly. The number of ASC specks increased and showed altered morphology in the blood of early-stage Parkinson's and Alzheimer's patients compared to controls, mimicking those found in the brain and cerebrospinal fluid. In serum samples we also measured the number of Aβ, p-tau and α-syn aggregates and formed a composite biomarker of (ASC + p-tau)/Aβ and (ASC + α-syn)/Aβ ratios that distinguished age-matched healthy controls from patients with early-stage Alzheimer's with AUC of 92% and early-stage Parkinson's with AUC of 97%. Our findings confirm ASC specks as a fluid candidate biomarker of inflammation for neurodegenerative diseases with blood being the main focus for further development as convenient sample for diagnostics and clinical trials.
Authors
- Caroline H. Williams‐Gray (ORCID: https://orcid.org/0000-0002-2648-9743)
- Maura Malpetti (ORCID: https://orcid.org/0000-0001-8923-9656)
- Kathy Triantafilou (ORCID: https://orcid.org/0000-0002-7473-6278)
- Yu P. Zhang (ORCID: https://orcid.org/0000-0001-5486-278X)
- Derya Emin (ORCID: https://orcid.org/0000-0002-3853-664X)
- James Benedict Rowe (ORCID: https://orcid.org/0000-0001-7216-8679)
- Annelies Quaegebeur (ORCID: https://orcid.org/0000-0001-5357-9341)
- David A. Klenerman (ORCID: https://orcid.org/0000-0001-7116-6954)
- Clare Elizabeth Bryant (ORCID: https://orcid.org/0000-0002-2924-0038)
- Martha Triantafilou (ORCID: https://orcid.org/0000-0002-8489-2602)
- Jack Brelstaff (ORCID: https://orcid.org/0000-0003-4772-8018)
- Henrik Zetterberg (ORCID: https://orcid.org/0000-0003-3930-4354)
- Lakmini Kahanawita
- Evgeniia Lobanova (ORCID: https://orcid.org/0000-0002-7605-5820)
Institutions
- University of Wisconsin–Madison (US)
- MRC Cognition and Brain Sciences Unit (GB)
- University of Cambridge (GB)
- University Hospital of Wales (GB)
- Sahlgrenska University Hospital (SE)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- UK Dementia Research Institute (GB)
- National Hospital for Neurology and Neurosurgery (GB)
- Addenbrooke's Hospital (GB)
- University College London (GB)
- Cardiff University (GB)
- University of Gothenburg (SE)
- Medical Research Council (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-11
- DOI
- https://doi.org/10.1038/s41467-024-53547-0
- Citations
- 25
- Primary Topic
- Tryptophan and brain disorders
- Type
- article
- Field-Weighted Citation Impact
- 3.93
Funders
- Wellcome Trust
- Alzheimer's Society
- National Institute for Health and Care Research
- Parkinson's UK
- University of Cambridge
- University College London
- European Commission
- Cambridge University Hospitals
- Vetenskapsrådet
- UK Dementia Research Institute
- HORIZON EUROPE Framework Programme
- Medical Research Council
- NIHR Cambridge Biomedical Research Centre