Abstract
Glial fibrillary acidic protein (GFAP) is a well-established biomarker of reactive astrogliosis in the central nervous system because of its elevated levels following brain injury and various neurological disorders. The advent of ultra-sensitive methods for measuring low-abundant proteins has significantly enhanced our understanding of GFAP levels in the serum or plasma of patients with diverse neurological diseases. Clinical studies have demonstrated that GFAP holds promise both as a diagnostic and prognostic biomarker, including but not limited to individuals with Alzheimer's disease. GFAP exhibits diverse forms and structures, herein referred to as its proteoform complexity, encompassing conformational dynamics, isoforms and post-translational modifications (PTMs). In this review, we explore how the proteoform complexity of GFAP influences its detection, which may affect the differential diagnostic performance of GFAP in different biological fluids and can provide valuable insights into underlying biological processes. Additionally, proteoforms are often disease-specific, and our review provides suggestions and highlights areas to focus on for the development of new assays for measuring GFAP, including isoforms, PTMs, discharge mechanisms, breakdown products, higher-order species and interacting partners. By addressing the knowledge gaps highlighted in this review, we aim to support the clinical translation and interpretation of GFAP in both CSF and blood and the development of reliable, reproducible and specific prognostic and diagnostic tests. To enhance disease pathology comprehension and optimise GFAP as a biomarker, a thorough understanding of detected proteoforms in biofluids is essential.
| Original language | English |
|---|---|
| Article number | e16226 |
| Pages (from-to) | 1-18 |
| Number of pages | 18 |
| Journal | Journal of Neurochemistry |
| Volume | 169 |
| Issue number | 1 |
| Early online date | 17 Sept 2024 |
| DOIs | |
| Publication status | Published - Jan 2025 |
Bibliographical note
© 2024 The Author(s). Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.Funding
This study is supported by the European Commission (Marie Curie International Training Network, grant agreement No 860197 (MIRIADE). MH and CT are recipients of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and Health Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). IV is supported by research grants from Amsterdam UMC and HealthHolland (a public-private partnership grant executed in collaboration with Olink and Quanterix). EH is a recipient of the following grants related to GFAP and astrocytes: Alzheimer NL (#WE.03- 2022-04), ZonMW MODEM dementia project (#10510032120006), EJP RD JTC 2019 (#463002004),\u2019la Caixa\u2019 Foundation (#LCF/PR/HR21/52410002). The research of SA is supported by Health-Holland). CT is the recipient of ABOARD, which is a public\u2010private partnership receiving funding from ZonMW (#73305095007) and HealthHolland, Topsector Life Sciences & Health (PPP\u2010allowance; #LSHM20106). More than 30 partners participate in ABOARD. ABOARD also receives funding from Edwin Bouw Fonds and Gieskes\u2010Strijbisfonds. CT has a collaboration contract with ADx Neurosciences, Quanterix and Eli Lilly, performed contract research or received grants from AC\u2010Immune, Axon Neurosciences, Biogen, Brainstorm Therapeutics, Celgene, EIP Pharma, Eisai, Olink, PeopleBio, Roche, Toyama, Vivoryon. CT serves on editorial boards of Medidact Neurologie/Springer, Alzheimer Research and Therapy, Neurology: Neuroimmunology & Neuroinflammation, and is editor of a Neuromethods book Springer. LV is supported by research grants from Amsterdam UMC, ZonMw, Stichting Diorapthe, and Olink and consultancy/speaking fees from Roche and Eli Lilly, all paid to her institution. Outside the submitted work: SA reports a patent pending; SA is in a consortium agreement with Cergentis BV as part of the TargetSV project; SA is in a consortium agreement with Olink and Quanterix as part of the NORMAL project. The rest of the authors do not have any competing interests to declare. This study is supported by the European Commission (Marie Curie International Training Network, grant agreement No 860197 (MIRIADE). MH and CT are recipients of ABOARD, which is a public\u2010private partnership receiving funding from ZonMW (#73305095007) and Health Holland, Topsector Life Sciences & Health (PPP\u2010allowance; #LSHM20106). IV is supported by research grants from Amsterdam UMC and HealthHolland (a public\u2010private partnership grant executed in collaboration with Olink and Quanterix). EH is a recipient of the following grants related to GFAP and astrocytes: Alzheimer NL (#WE.03\u2010 2022\u201004), ZonMW MODEM dementia project (#10510032120006), EJP RD JTC 2019 (#463002004),\u2019la Caixa\u2019 Foundation (#LCF/PR/HR21/52410002). The research of SA is supported by Health\u2010Holland).
| Funders | Funder number |
|---|---|
| Health Holland | |
| Edwin Bouw Fonds and Gieskes‐Strijbisfonds | |
| Health‐Holland | |
| Eli Lilly and Company | |
| Topsector Life Sciences & Health | |
| Roche | |
| ZonMw | |
| Amsterdam University Medical Centers | |
| HealthHolland | |
| ’la Caixa’ Foundation | #LCF/PR/HR21/52410002 |
| Alzheimer NL | 10510032120006, 463002004, .03- 2022-04 |
| European Commission | 860197 |
| European Commission |