Beta-synuclein in cerebrospinal fluid as an early diagnostic marker of Alzheimer’s disease

Abstract

ObjectiveSynaptic loss plays a major role in Alzheimer’s disease (AD). However so far no neurochemical marker for synaptic loss has been introduced into clinical routine. By mass spectrometry beta-synuclein was established as a candidate marker. We now aimed to set up a novel ELISA for beta-synuclein for evaluation of its potential as a diagnostic and predictive marker for AD.MethodsWe analysed in total 393 patients from four specialised centres. The diagnostic groups comprised: AD (n=151), behavioural variant frontotemporal dementia (bvFTD, n=18), Parkinson syndrome (n=46), Creutzfeldt-Jakob disease (CJD, n=23), amyotrophic lateral sclerosis (ALS, n=29), disease control (n=66) and 60 non-neurodegenerative control patients. Results were compared with core AD biomarkers (total tau, phospho-tau and amyloid-β peptide 1–42). Additionally, coexistence of beta-synuclein with vesicular glutamate transporter 1 (VGLUT1) was determined and beta-synuclein levels were quantified in brain homogenates.ResultsBeta-synuclein levels quantified with the newly established ELISA correlated strongly with antibody-free quantitative mass spectrometry data (r=0.92 (95% CI: 0.89 to 0.94), p<0.0001). Cerebrospinal fluid (CSF) beta-synuclein levels were increased in AD-mild cognitive impairment (p<0.0001), AD dementia (p<0.0001) and CJD (p<0.0001), but not in bvFTD, Parkinson syndrome or ALS. Furthermore, beta-synuclein was localised in VGLUT1-positive glutamatergic synapses, and its expression was significantly reduced in brain tissue from patients with AD (p<0.01).ConclusionWe successfully established a sensitive and robust ELISA for the measurement of brain-enriched beta-synuclein, which we could show is localised in glutamatergic synapses. We confirmed previous, mass spectrometry-based observations of increased beta-synuclein levels in CSF of patients with AD and CJD supporting its potential use as a marker of synaptic degeneration.

Microdissected Pyramidal Cell Proteomics of Alzheimer Brain Reveals Alterations in Creatine Kinase B-Type, 14-3-3-γ, and Heat Shock Cognate 71

“…There was a clear clustering in the general proteome of AD (red symbols) vs. control (blue), p = 0.0023 (Figure 2). The top 10 proteins with the most differences in level between AD and control (excluding keratin which is a contaminant) included the previously well-studied inflammatory marker, glial fibrillary protein (GFAP) (Laurent et al, 2018), and several markers of neurodegeneration; neurofilament light polypeptide (NfL), microtubule-associated protein-2 (MAP2), spectrin βchain and β-chain, and β-synuclein (Yan et al, 2012;Bacioglu et al, 2016;Halbgebauer et al, 2020). Although not largely studied in AD, malate dehydrogenase expression has been explored in different brain regions of AD previously (Zahid et al, 2014), thus we selected CKB, Hsc71, and 14-3-3-γ for downstream analyses since, to our knowledge, these proteins have been less studied in AD human brain tissue.…”

From Cerebrospinal Fluid Neurochemistry to Clinical Diagnosis of Alzheimer’s Disease in the Era of Anti-Amyloid Treatments. Report of Four Patients

“…Recent evidence suggests that α-, and also βand γ-synuclein, may be effective markers of AD rather than synucleinopathy [82]. Both αand β-synuclein may be early markers of AD, even in non-demented elder subjects [83,84], while the ratio of total tau/α-synuclein may serve as a marker of tau phosphorylation, even allowing patients with the A − T + (N + ) profile to re-enter the AD diagnostic group [85]. Blood-based classical [86,87] and exosomal [88] biomarkers may prove helpful, especially for frequent monitoring of the biochemical effects of anti-amyloid antibodies.…”

Mass spectrometry‐based methods for robust measurement of Alzheimer's disease biomarkers in biological fluids

“…Additionally, the other member of the synuclein family, β-synuclein, was proposed as a new candidate marker of synaptic loss. When measured by mass spectrometric assay, β-synuclein was highly increased in CSF and serum of patients with AD compared with age-matched controls and other neurodegenerative diseases (Halbgebauer et al, 2020;Oeckl et al, 2016Oeckl et al, , 2020.…”