Specific serum antibody binding to phosphorylated and non-phosphorylated tau in non-cognitively impaired, mildly cognitively impaired, and Alzheimer’s disease subjects: an exploratory study

Abstract

BackgroundTau vaccination and administration of anti-tau antibodies can prevent pathology and cognitive impairment in transgenic mouse models of tauopathy, suggesting that therapies which increase anti-tau antibodies might slow the development and/or progression of Alzheimer’s disease (AD). The extent to which individuals with no cognitive impairment (NCI) possess serum anti-tau antibodies, and whether their concentrations of these antibodies differ from anti-tau antibody levels in persons with mild cognitive impairment (MCI) or AD, are unclear. Previous studies measuring these antibodies did not account for antibody polyvalent binding, which can be extensive, nor that antibody binding to phosphorylated tau peptides could be due to binding to non-phosphorylated epitopes on those peptides.MethodsAn ELISA controlling for these factors was used to measure the specific binding of serum IgG and IgM to phosphorylated (“pTau;” phosphorylated at Serine-199 and Serine-202) and non-phosphorylated (“non-pTau”) tau 196-207 in subjects with NCI, MCI, or AD (n = 10/group). Between-group differences in these antibody levels were evaluated for statistical significance, and correlations were examined in pooled data from all subjects between these antibody levels and subject age, global cognitive functioning, and NFT counts.ResultsSpecific IgG binding to pTau and non-pTau was detected in all subjects except for one NCI control. Specific IgM binding was detected to pTau in all subjects except for two AD patients, and to non-pTau in all subjects. Mean pTau IgG was increased in MCI subjects by 53% and 70% vs. AD and NCI subjects respectively (both p < 0.05), while no significant differences were found between groups for non-pTau IgG (p = 0.052), pTau IgM, or non-pTau IgM. Non-pTau IgG was negatively associated with global cognition (Spearman rho = −0.50).ConclusionsSpecific binding of serum IgG and IgM to phosphorylated and non-phosphorylated tau may be present in older persons regardless of their cognitive status. Serum IgG to phosphorylated tau may be increased in individuals with MCI, but this unexpected finding requires confirmation. The approach used in this study to measure specific serum antibodies to phosphorylated tau should be useful for measuring antibodies to other post-translationally-modified proteins that are of relevance to neurodegenerative disorders.

Tau-Reactive Endogenous Antibodies: Origin, Functionality, and Implications for the Pathophysiology of Alzheimer’s Disease

“…Antibodies directed against tau protein are also shown in various intravenous immunoglobulin (IVIG) products and pooled immunoglobulin subtype G from large cohorts of healthy donors [64–68]. Quantitative evaluation of tau-reactive antibodies in the blood has been reported by several groups [54–57, 60–62]. Even though different tau variants have been used as antigens in ELISA reports in these publications, surprisingly, no statistically significant differences were found between healthy controls and AD patients.…”

“…Only higher levels of tau-reactive antibodies were detected with respect to gender in MCI due to the AD group [56]. Klaver and colleagues demonstrated elevated titers of serum tau-reactive antibodies against tau fragment 196-207 phosphorylated at residues 199/202 in a group of MCI subjects [62]. Remarkably, in several trials, the levels of tau-reactive antibodies in the serum of AD patients were lower compared to controls and decline further with the advancement of the pathology [60].…”

Autoantibodies targeting neuronal proteins as biomarkers for neurodegenerative diseases

“…Klaver et al tested the binding of IgG and IgM from AD, MCI, and control subjects to p-tau and tau, using as antigens 196-207 tau peptide, as well as full-length variants (tau and p-tau at Serine-199 and Serine-202). Authors found specific antibodies to both p-tau and tau in most subjects, regardless of cognitive status, with increased specific IgG binding to p-tau (an increase in the p-tau IgG ratio) detected in MCI subjects as compared to AD patients and healthy controls 80 .…”

Role of Specific Autoantibodies in Neurodegenerative Diseases: Pathogenic Antibodies or Promising Biomarkers for Diagnosis

“…In addition to Aβ Aabs in AD, tau Aabs have also been found in the sera and CSF of AD patients and healthy subjects [41][42][43][44][45]. The tau protein has many possible phosphorylation sites.…”