Novel autoimmune response in a tauopathy mouse model

Carlos J. Nogueras-Ortiz,Irving E. Vega,Jaime Vaquer-Alicea,Hector J. De Jesús-Cortes

doi:10.3389/fnins.2013.00277

Carlos J. Nogueras-Ortiz, Irving E. Vega + Show 2 more

Open Access

https://doi.org/10.3389/fnins.2013.00277

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Abstract

Molecular diagnostic tools with non-invasive properties that allow detection of pathological events in Alzheimer's disease (AD) and other neurodegenerative tauopathies are essential for the development of therapeutics. Several diagnostic strategies based on the identification of biomarkers have been proposed. However, its specificity among neurodegenerative disorders is disputable as the association with pathological events remains elusive. Recently, we showed that Amphiphysin-1 (AMPH1) protein's abundance is reduced in the central nervous system (CNS) of the tauopathy mouse model JNPL3 and AD brains. AMPH1 is a synaptic protein that plays an important role in clathrin-mediated endocytosis and associates with BIN1, one of the most important risk loci for AD. Also, it has been associated with a rare neurological disease known as Stiff-Person Syndrome (SPS). Auto-antibodies against AMPH1 are used as diagnostic biomarkers for a paraneoplastic variant of SPS. Therefore, we set up to evaluate the presence and abundance of auto-AMPH1 antibodies in tau-mediated neurodegeneration. Immunoblots and enzyme-linked immunosorbent assays (ELISA) were conducted to detect the presence of auto-AMPH1 antibodies in sera from euthanized mice that developed neurodegeneration (JNPL3) and healthy control mice (NTg). Results showed increased levels of auto-AMPH1 antibodies in JNPL3 sera compared to NTg controls. The abundance of auto-AMPH1 antibodies correlated with motor impairment and AMPH1 protein level decrease in the CNS. The results suggest that auto-AMPH1 antibodies could serve as a biomarker for the progression of tau-mediated neurodegeneration in JNPL3 mice.

Highlights

Tauopathies are a group of neurodegenerative disorders that present cognitive and/or motor deficits associated to modifications and oligomerization of the microtubule-associated protein tau
Based on the fact that auto-AMPH1 antibodies are used as diagnostic tool in Stiff-Person Syndrome (SPS), we set to study the presence of auto-AMPH1 antibodies in the serum of JNPL3 mice, using recombinant AMPH1 as “bait.” Serum obtained from a 12 month old terminally ill JNPL3 mouse with reduced abundance of AMPH1 protein in the spinal cord (Figure 1A) was used for immunoblot assays; serum from a NTg littermate with normal protein levels of AMPH1 was used as control (Figure 1A)
Motor impairment correlates with the abundance of tau aggregates known as neurofibrillary tangles (NFTs) which are considered to be the pathological hallmark in Alzheimer’s disease (AD) and related disorders

Summary

Introduction

Tauopathies are a group of neurodegenerative disorders that present cognitive and/or motor deficits associated to modifications and oligomerization of the microtubule-associated protein tau. Alzheimer’s disease (AD) is the most common and intensively studied tauopathy because of its prevalence, severity, and care costs (Steenland et al, 2009). These facts instigate special attention to AD’s etiology and associated molecular mechanisms to identify potential diagnostic and therapeutic strategies. It is imperative to identify accurate biomarkers of tau-mediated neurodegeneration with non-invasive properties in order to develop definitive diagnostic tools for AD and related disorders

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