Abstract
In the present work, the concentrations of Aβ11-x and Aβ17-x peptides (x=40 or 42), which result from the combined cleavages of β-amyloid precursor protein (AβPP) by β'/α or α/γ-secretases, respectively, were assessed in cerebrospinal fluid (CSF) samples from patients with Alzheimer's disease (AD) or mild cognitive impairment (MCI). Specific multiplexed assays were set up using new anti-40 and anti-42 monoclonal antibodies (mAbs) for the capture of these N-truncated Aβ peptides and anti-11 or anti-17 mAbs for their detection. The specificity, sensitivity and reproducibility of such assays were assessed using synthetic peptides and human cell models. Aβ11-x and Aβ17-x were then measured in CSF samples from patients with AD (n=23), MCI (n=23) and controls with normal cognition (n=21). Aβ11-x levels were significantly lower in patients with MCI than in controls. Compared with the combined quantification of Aβ1-42, total Tau (T-Tau) and phosphorylated Tau (P-Tau; AlzBio3, Innogenetics), the association of Aβ11-40, Aβ17-40 and T-Tau improved the discrimination between MCI and controls. Furthermore, when patients with MCI were classified into two subgroups (MCI ⩽1.5 or ⩾2 based on their CDR-SB (Cognitive Dementia Rating–Sum of Boxes) score), the CSF Aβ17-40/Aβ11-40 ratio was significantly higher in patients with CDR-SB ⩽1.5 than in controls, whereas neither Aβ1-42, T-Tau nor P-Tau allowed the detection of this subpopulation. These results need to be confirmed in a larger clinical prospective cohort.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia and is characterized by loss of memory and progressive cognitive impairment
We produced specific anti-40 (6H7) and anti-42 (12E8) monoclonal antibodies (mAbs) that displayed high affinity toward their corresponding synthetic peptides and exclusive specificity as no significant crossreaction toward other C-terminal truncated Ab peptides was observed by surface plasmon resonance analyses (Supplementary Table S1)
This study highlights for the first time the potential diagnostic value of the cerebrospinal fluid (CSF) concentration of Ab11-40, Ab11-42, Ab17-40 and Ab17-42 peptides for early AD detection and mild cognitive impairment (MCI) characterization
Summary
Alzheimer’s disease (AD) is the most common form of dementia and is characterized by loss of memory and progressive cognitive impairment. The major histopathological hallmarks of AD are extracellular senile plaques, which mainly consist of b-amyloid peptides (Ab),[1] and intracellular neurofibrillary tangles, which are mostly composed of hyperphosphorylated microtubule-associated Tau protein.[2,3] Accumulation of Ab peptide aggregates could lead to hippocampal synaptic dysfunction,[4] thereby explaining the AD memory deficits. Episodic memory loss is generally considered as the core requirement for the diagnosis of mild cognitive impairment (MCI).[5,6] Early and reliable AD diagnosis at the stage of MCI would improve AD prognosis and provide the means to examine the putative efficacy of newly designed drugs as disease modifiers. The combined measurement of total Tau (T-Tau), phosphorylated Tau (P-Tau) and Ab1-42 in cerebrospinal fluid (CSF) allows the best biochemical characterization of the patients’ clinical status, even from a prognostic point of view.[7,8,9,10,11,12] despite their good diagnostic performance, we clearly need complementary biomarkers to differentiate between AD and non-AD disorders,[13,14,15] at early stages (MCI)
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