Mohaupt et al. Alzheimer’s Research & Therapy (2022) 14:179 https://doi.org/10.1186/s13195-022-01125-1 MINI REVIEW Open Access β‑Synuclein as a candidate blood biomarker for synaptic degeneration in Alzheimer’s disease Pablo Mohaupt1, Marie‑Laure Pons1, Jérôme Vialaret1, Constance Delaby1,2, Christophe Hirtz1* and Sylvain Lehmann1 Abstract Synaptic degeneration is an early event closely associated with the course of Alzheimer’s disease (AD). The identifica‑ tion of synaptic blood biomarkers is, therefore, of great interest and clinical relevance. The levels of most synaptic pro‑ teins are increased in the cerebrospinal fluid (CSF) of patients with AD, but their detection in blood is hitherto either unavailable or not very informative. This paradigm is related to their low concentration, their peripheral origin, or the presence of highly abundant blood proteins that hinder detection. In recent years, significant progress has been made in detecting the presynaptic protein β-synuclein. This mini-review summarizes the results that highlight the role of β-synuclein as a candidate blood marker for synaptic degeneration in AD. Keywords: β-Synuclein, Alzheimer’s disease, Blood biomarker, Synaptic dysfunction Background also a clinical need for biomarkers that detect AD in its The etiology of Alzheimer’s disease (AD) remains con- earliest stages and predict and monitor disease progres- troversial, despite recent developments in genetics and sion [6]. Synaptic degeneration is the neuropathological cell biology. AD is characterized by neuronal loss, extra- hallmark most highly correlated with cognitive impair- cellular amyloid-β plaques, and neurofibrillary tangles ment in AD; hence, the interest in synaptic biomark- consisting of strings of hyperphosphorylated tau located ers that may complement the amyloid and tau panels within neurons [1]. Until recently, only therapies were already in use (Fig. 1) [7]. Synaptic degeneration in AD available to treat the symptoms of AD, and clinical tri- can already be determined by quantifying post- and pre- als building on the amyloid cascade theorem struggled synaptic proteins in CSF and by measuring the levels of to halt or delay disease progression [2, 3]. Anti-tau anti- SV2A with positron emission tomography (PET) [8, 9]. bodies have so far been unsuccessful, whereas the anti- The measurement of brain-specific synaptic proteins in amyloid-beta antibody aducanumab was approved by the blood is currently not available but can be of great rel- Food and Drug Administration (FDA). This treatment is evance for clinical trials, disease monitoring, and early supposed to target the underlying disease process of AD, diagnosis. Here, we summarize recent findings and out- while its effectiveness is moderate but controversial [4]. line the rationale that the presynaptic protein β-synuclein Thus, there is still a need for more effective or targeted is an early and prognostic blood marker for AD. approaches and to unravel the pathophysiological sub- types of AD [5]. As treatments become available, there is β‑Synuclein in Alzheimer´s disease β-Synuclein is a presynaptic protein encoded by the synuclein Beta locus (SNCB) and is predominantly *Correspondence: christophe.hirtz@umontpellier.fr expressed in the brain. β-Synuclein forms, together 1 LBPC-PPC, Université de Montpellier, IRMB CHU de Montpellier, INM INSERM, with α-synuclein and γ-synuclein, a group of proteins Montpellier, France dubbed “Synucleins” and is shown to inhibit α-synuclein Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. The Creative Commons Public Domain Dedication waiver (http://​creat​iveco​ mmons.​org/​publi​cdoma​in/​zero/1.​0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Mohaupt et al. Alzheimer’s Research & Therapy (2022) 14:179 Page 2 of 4 Fig. 1 Pathophysiological hallmarks of Alzheimer’s disease and its associated biomarkers in either blood or cerebrospinal fluid. Alzheimer’s disease is characterized by amyloid plaques, neurofibrillary tangles, axonal damage, microglial activation, and synaptic dysfunction. These pathophysiological hallmarks are responsible for significant modification of CSF Amyloid-β42/40 ratio, levels of tau with abnormal phosphorylation at positions 181, 231, and 217, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) levels. These variations are also detected in the blood of AD patients. The levels of numerous proteins involved in synaptic function vary in CSF in (preclinical) AD. Proteins originating from the central nervous system are often present in low concentrations that are difficult to detect. A fraction of synaptic proteins is also expressed in other tissues and are therefore not suitable as specific blood biomarkers for synaptic dysfunction. To date, β-synuclein, whose expression is brain-specific, is the only synaptic protein that is determined to be significantly increased in the blood of AD patients aggregation [10]. α-Synuclein is extensively researched to (DLB), and multiple system atrophy (MSA), which are assess its biomarker potential in synucleinopathies such characterized by abnormal accumulation of α-synuclein as Parkinson’s disease (PD), dementia with Lewy bodies aggregates [11]. As such, the presence of elevated Mohaupt et al. Alzheimer’s Research & Therapy (2022) 14:179 Page 3 of 4 β-synuclein in the CSF of AD patients was first detected the presynaptic SYT-1 and SNAP-25, the postsynap- serendipitously in an endeavor to identify abnormalities tic Ng, and NPTXs which are present in both pre- and specific to a particular synucleinopathy [12]. A signifi- post-synapses all show altered levels in CSF [20–23]. cant increase with a high correlation with CSF tau was Nonetheless, most synaptic proteins are not yet assayable observed in AD and Creutzfeldt-Jakob disease (CJD). Of in the blood, even with ultrasensitive methods as tested note, β-synuclein was slightly higher in dementia with recently for SNAP-25 [24]. Ng can be detected in blood, DLB and PD-related dementia compared with controls but its expression is not restricted to the brain; therefore, and PD without dementia, suggesting that β-synuclein the changes observed in CSF are not specifically reflected may be more associated with cognitive impairment than in the blood [9]. with motor impairment. The increase of β-synuclein in The combined results outlined in this mini-review AD CSF was also observed in a study targeting synaptic show that β-synuclein could potentially complement the proteins with mass spectrometry and was confirmed in panel of blood biomarkers for AD as a marker for synap- an immunodetection study [13, 14]. The latter suggests tic degeneration, whereas phosphorylated tau biomarkers that β-synuclein is altered more specifically in amyloi- reflect amyloidopathy and tau-pathology. dopathies, as no changes were observed in non-amyloid pathologies such as frontotemporal dementia (FTD). Conclusion Furthermore, the increase was already present in prodro- In conclusion, β-synuclein is to date the only detectable mal patients with mild cognitive impairment (MCI-AD), blood biomarker for synaptic degeneration in AD. The highlighting its potential as an early diagnostic and prog- switch from mass spectrometry to an immunodetection nostic biomarker candidate. The AD-specific increase method increases the accessibility of β-synuclein quanti- was also observed in a study researching synaptic dys- fication in larger research cohorts. Its value as a marker function in different neurodegenerative diseases [15]. A for AD will have to be tested in cohorts and compared major step in assessing the value of β-synuclein as a bio- with blood markers such as pTau217 and pTau231, whose marker for AD was the development of an immunopre- performances remain unmatched to date [25]. cipitation mass spectrometry (IP-MS) method that can be applied in both CSF and blood [16]. This novel assay Abbreviations confirmed the previous results obtained in CSF and, in Aβ40: Amyloid-β 40; Aβ42: Amyloid-β 42; AD: Alzheimer’s disease; CJD: particular, showed that the levels of β-synuclein were Creutzfeldt-Jakob disease; CSF: Cerebrospinal fluid; DS: Down syndrome; also significantly higher in the blood of AD patients. This FDA: Food and Drug Administration; GAP-43: Axonal membrane protein GAP-43; GFAP: Glial fibrillary acidic protein; GluR4: Glutamate receptor 4; IP-MS: study positioned β-synuclein as the first synaptic blood Immunoprecipitation followed by mass spectrometry; MCI-AD: Mild cogni‑ biomarker for AD. The increase in MCI-AD was more tive impairment due to AD; NfL: Neurofilament light chain; Ng: Neurogranin; moderate and did not reach significance, but this is likely NPTX1: Neuronal pentraxin-1; NPTXs: Neuronal pentraxins; NRXN: Neurexin; PD: Parkinson’s disease; PET: Positron emission tomography; PSD-95: Post‑ due to the small cohort size. The increase was also con- synaptic density protein 95; pTau181: Tau with phosphorylation at positions firmed in a study in adults with Down syndrome (DS), 181; pTau217: Tau with phosphorylation at positions 217; pTau231: Tau with who are at high risk of developing AD due to overexpres- phosphorylation at positions 231; SNAP-25: Synaptosomal-associated protein 25; SNCB: Synuclein Beta locus; SV2A: Synaptic vesicle glycoprotein 2A; STX1B: sion of the APP gene located on chromosome 21 [17]. Of Syntaxin-1B; SYT-1: Synaptotagmin-1; Thy-1: Thy-1 membrane glycoprotein; particular note, β-synuclein was already altered in pre- TREM2: Triggering receptor expressed on myeloid cells 2. clinical AD and was elevated earlier than pTau181, con- Acknowledgements firming its early diagnostic and prognostic interest. More Not applicable. recently, blood β-synuclein levels were found to corre- late with cognitive impairment and brain atrophy in AD, Authors’ contributions P.M. and S.L. conceptually designed the work. P.M., M.P., J.V., C.D., and S.L. wrote which indicates its association with disease severity [18]. the manuscript. P.M. made the illustration. C.H. and S.L reviewed the manu‑ The IP-MS analytical approach is innovative but script. All authors read, approved and commented on the manuscript. requires large blood sample volumes and has low turno- Funding ver, hindering the analysis of large cohorts and routine This project has received funding (support for PM and the laboratory) from the use. Recently, an ultrasensitive immunodetection assay European Union’s Horizon 2020 research and innovation program under the with Simoa was developed to target β-synuclein in blood Marie Skłodowska-Curie grant agreement No 860197 MIRIADE. [19]. So far, this test has been applied to CJD and it has Availability of data and materials yet to be determined if this assay can match the clinical Not applicable. performance of IP-MS in AD-related cohorts. There is no comparison of blood β-synuclein with Declarations other synaptic markers such as SNAP-25, SYT-1, neu- Ethics approval and consent to participate ronal pentraxins (NPTXs), or neurogranin (Ng). Indeed, Not applicable. Mohaupt et al. Alzheimer’s Research & Therapy (2022) 14:179 Page 4 of 4 Consent for publication 17. Oeckl P, Wagemann O, Halbgebauer S, Anderl-Straub S, Nuebling G, Prix The figure is original, created with BioRe​nder.​com. C, et al. Serum beta-synuclein is higher in Down syndrome and precedes rise of pTau181. Ann Neurol. 2022;92:6–10. Competing interests 18. Oeckl P, Anderl-Straub S, Danek A, Diehl-Schmid J, Fassbender K, Fliess‑ The authors declare no competing interests. bach K, et al. Relationship of serum beta-synuclein with blood biomarkers and brain atrophy. Alzheimers Dementia. 2022;1–14. Author details 19. Halbgebauer S, Abu-Rumeileh S, Oeckl P, Steinacker P, Roselli F, Wiesner D, 1 LBPC-PPC, Université de Montpellier, IRMB CHU de Montpellier, INM INSERM, et al. Blood β-synuclein and neurofilament light chain during the course Montpellier, France. 2 Sant Pau Memory Unit, Hospital de la Santa Creu i Sant of prion disease. Neurology. 2022;98:e1434–45. Pau - Biomedical Research Institute Sant Pau - Universitat Autònoma de Barce‑ 20. Brinkmalm A, Brinkmalm G, Honer WG, Frölich L, Hausner L, Minthon L, lona, Barcelona, Spain. et al. SNAP-25 is a promising novel cerebrospinal fluid biomarker for syn‑ apse degeneration in Alzheimer’s disease. Mol Neurodegener. 2014;9:53. Received: 6 September 2022 Accepted: 17 November 2022 21. Öhrfelt A, Brinkmalm A, Dumurgier J, Brinkmalm G, Hansson O, Zet‑ terberg H, et al. The pre-synaptic vesicle protein synaptotagmin is a novel biomarker for Alzheimer’s disease. Alzheimers Res Ther. 2016;8:41. 22. Mavroudis IA, Petridis F, Chatzikonstantinou S, Kazis D. A meta-analysis on CSF neurogranin levels for the diagnosis of Alzheimer’s disease and mild References cognitive impairment. Aging Clin Exp Res. 2020;32:1639–46. 1. Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypoth‑ 23. de San G, José N, Massa F, Halbgebauer S, Oeckl P, Steinacker P, et al. esis. Science. 1992;256:184–5. Neuronal pentraxins as biomarkers of synaptic activity: from physiologi‑ 2. Huang L-K, Chao S-P, Hu C-J. Clinical trials of new drugs for Alzheimer cal functions to pathological changes in neurodegeneration. J Neural disease. J Biomed Sci. 2020;27:18. Transm. 2022;129:207–30. 3. Mangialasche F, Solomon A, Winblad B, Mecocci P, Kivipelto M. Alz‑ 24. Nilsson J, Ashton NJ, Benedet AL, Montoliu-Gaya L, Gobom J, Pascoal heimer’s disease: clinical trials and drug development. Lancet Neurol. TA, et al. Quantification of SNAP-25 with mass spectrometry and Simoa: 2010;9:702–16. a method comparison in Alzheimer’s disease. Alzheimers Res Ther. 4. Kuller LH, Lopez OL. ENGAGE and EMERGE: truth and consequences? 2022;14:78. Alzheimers Dement. 2021;17:692–5. 25. Milà-Alomà M, Ashton NJ, Shekari M, Salvadó G, Ortiz-Romero P, 5. Tijms BM, Gobom J, Reus L, Jansen I, Hong S, Dobricic V, et al. Pathophysi‑ Montoliu-Gaya L, et al. Plasma p-tau231 and p-tau217 as state markers ological subtypes of Alzheimer’s disease based on cerebrospinal fluid of amyloid-β pathology in preclinical Alzheimer’s disease. Nat Med. proteomics. Brain. 2020;143:3776–92. 2022;28(9):1797–801. 6. Mavrina E, Kimble L, Waury K, Gogishvili D, de San G, José N, et al. Multi- omics interdisciplinary research integration to accelerate dementia biomarker development (MIRIADE). Front Neurol. 2022;13:890638 Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub‑ 7. Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, et al. Physical lished maps and institutional affiliations. basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991;30:572–80. 8. Chen M-K, Mecca AP, Naganawa M, Finnema SJ, Toyonaga T, Lin S-F, et al. Assessing synaptic density in Alzheimer disease with synaptic vesicle glycoprotein 2A positron emission tomographic imaging. JAMA Neurol. 2018;75:1215–24. 9. Kvartsberg H, Portelius E, Andreasson U, Brinkmalm G, Hellwig K, Lelental N, et al. Characterization of the postsynaptic protein neurogranin in paired cerebrospinal fluid and plasma samples from Alzheimer’s disease patients and healthy controls. Alzheimers Res Ther. 2015;7:40. 10. Hashimoto M, Rockenstein E, Mante M, Mallory M, Masliah E. β-Synuclein inhibits α-synuclein aggregation: a possible role as an anti-parkinsonian factor. Neuron. 2001;32:213–23. 11. Pons M-L, Loftus N, Vialaret J, Moreau S, Lehmann S, Hirtz C. Proteom‑ ics challenges for the assessment of synuclein proteoforms as clinical biomarkers in Parkinson’s disease. Front Aging Neurosci. 2022;14:818606. 12. Oeckl P, Metzger F, Nagl M, von Arnim CAF, Halbgebauer S, Steinacker P, et al. Alpha-, beta-, and gamma-synuclein quantification in cerebrospinal fluid by multiple reaction monitoring reveals increased concentrations in Alzheimer’s and Creutzfeldt-Jakob disease but no alteration in synucle‑ inopathies Mol Cell Proteomics. 2016;15:3126–38. 13. Halbgebauer S, Oeckl P, Steinacker P, Yilmazer-Hanke D, Anderl-Straub S, von Arnim C, et al. Beta-synuclein in cerebrospinal fluid as an early Ready to submit your research ? Choose BMC and benefit from: diagnostic marker of Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2021;92:349–56. • fast, convenient online submission 14. Nilsson J, Gobom J, Sjödin S, Brinkmalm G, Ashton NJ, Svensson J, et al. Cerebrospinal fluid biomarker panel for synaptic dysfunction in Alzhei‑ • thorough peer review by experienced researchers in your field mer’s disease. Alzheimers Dementia. 2021;13:e12179. • rapid publication on acceptance 15. Nilsson J, Cousins KAQ, Gobom J, Portelius E, Chen-Plotkin A, Shaw LM, • support for research data, including large and complex data types et al. Cerebrospinal fluid biomarker panel of synaptic dysfunction in Alzheimer’s disease and other neurodegenerative disorders. Alzheimers • gold Open Access which fosters wider collaboration and increased citations Dement. 2022;1–10. • maximum visibility for your research: over 100M website views per year 16. Oeckl P, Halbgebauer S, Anderl-Straub S, von Arnim CAF, Diehl-Schmid J, Froelich L, et al. Targeted mass spectrometry suggests beta-synuclein At BMC, research is always in progress. as synaptic blood marker in Alzheimer’s disease. J Proteome Res. 2020;19:1310–8. Learn more biomedcentral.com/submissions