Elevation of microtubule-associated protein tau in the cerebrospinal fluid of patients with Alzheimer's disease

Abstract

Currently, there is no biochemical marker clinically available to test for the presence of Alzheimer's disease (AD). Recent studies suggest that the core component of AD-associated neurofibrillary tangles (NFTs), the microtubule-associated protein tau, might be present in CSF. This study focuses on establishing both the presence of tau in CSF and its potential utility in the diagnosis of AD. We obtained CSF from 181 individuals; 71 of these were diagnosed as having probable AD by NINCDS-ADRDA criteria. The remaining 110 individuals were divided into three groups: (1) age-matched demented non-AD patients (n = 25), (2) neurologic controls (n = 59), and (3) other controls (n = 26). We developed a sensitive enzyme-linked immunosorbent tau assay using monoclonal antibodies prepared against recombinant human tau. We confirmed specificity of the antibodies by a combination of immunoprecipitation and immunoblot results. By this assay we measured that the AD population has a mean level of tau 50% greater than the non-AD dementia patients. Comparing AD patients with all other groups, the difference in tau levels as analyzed by one-way ANOVA is highly statistically significant (p < 0.001). Postmortem analysis of two AD patients with high levels of CSF tau revealed a high density of NFTs in the hippocampus. There was no significant correlation between tau and age in the non-AD groups. This study suggests that CSF tau is elevated in AD and might be a useful aid in antemortem diagnosis.

Cerebrospinal fluid protein biomarkers for Alzheimer’s disease

“…As shown in Table 1, four different ELISA methods for quantification of T-tau have been published. [13][14][15][16] A moderate to marked increase in CSF T-tau in AD has consistently been found in numerous publications. 17 The first paper on CSF T-tau as a protein biomarker for AD used an ELISA method with a polyclonal reporter antibody and found a very marked increase in CSF T-tau in AD.…”

“…Most studies have found normal to mildly increased CSF T-tau levels in other dementias, such as frontotemporal dementia (FTD) 14,15,21,50,52,69,70,73,[82][83][84][85][86] and Lewy body dementia (LBD). [85][86][87][88][89][90] Other than in aged nondemented individuals, normal CSF T-tau is found in depression, alcoholic dementia, and in chronic neurological disorders such as Parkinson's disease (PD) and progressive supranuclear palsy.…”

Brain-specific proteins in cerebrospinal fluid for the diagnosis of neurodegenerative diseases

“…40 Other studies reported the presence of (near to) full-length tau proteins in CSF. 29,37 Given the now widely accepted concept of increased tau and decreased Ab 42 concentrations in AD CSF, it was a logical step to analyse the characteristics of the combined analysis of these biomarkers for the diagnosis of AD versus other dementia syndromes. In several studies the sensitivity and speci¢city of the combined analysis of CSF Ab 42 and tau has been calculated (see Table 3).…”

Hyperphosphorylated tau protein in the cerebrospinal fluid of patients with Alzheimer's disease and other dementias: preliminary findings

“…In mature CNS low phosphorylated forms of tau protein predominate, maintaining adequate neuronal homeostasis. PHF-tau concentrations has been shown to be elevated in the cortex of AD patients while normal tau concentration is decreased 8 . Considering early and accurate diagnosis and differential diagnosis with other dementias that mimic AD symptoms, the development of a biological marker is of great value.…”

“…Many groups have shown an increase in tau levels 4,5,8,10,12,13 and a decrease in Aβ42 levels 13,14,15 in the CSF of AD patients when compared to non-demented elderly controls. The more recent longitudinal studies use the combination of high tau and low Aβ42 to correlate their levels to the stage of the disease 13,15 .…”