Autoantibodies to the adenosine triphosphate synthase play a pathogenetic role in Alzheimer's disease

Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanità, Rome, Italy.
Neurobiology of aging (Impact Factor: 5.01). 04/2012; 33(4):753-66. DOI: 10.1016/j.neurobiolaging.2010.05.013
Source: PubMed


It has become evident that an autoimmune component could play a role in Alzheimer's disease (AD) onset and/or progression. The aim of this study was to identify neuronal antigenic targets specifically recognized by serum autoantibodies and to investigate their cellular effects and their possible pathogenetic role. We identified, by an immunoproteomic approach using mouse brain proteins, the adenosine triphosphate (ATP) synthase β subunit as a new autoantigen in AD. Using an ELISA assay we found that serum anti-ATP synthase autoantibodies were present in 38% of patients with AD, but in no age-matched healthy subjects or in patients with Parkinson's disease or atherosclerosis. Analytical cytology studies, using SH-SY5Y neuroblastoma cell line, showed that ATP synthase autoantibodies were capable of inducing the inhibition of ATP synthesis, alterations of mitochondrial homeostasis and cell death by apoptosis. These findings suggest that autoantibodies specific to ATP synthase can exert a pathogenetic role via a mechanism that brings into play the impairment of the extracellular ATP homeostasis and the alteration of mitochondrial function triggering cell death by apoptosis.

Download full-text


Available from: Maurizio Sorice, Nov 17, 2014
  • Source
    • "In method B (Harris et al. 2005) plasma membranes, collapsed over the nuclei, were separated as floating membranes by isopycnic centrifugation using 2 M sucrose (PMB). Considering that the ectopic enzyme is mainly localized in lipid rafts composed of cholesterol and sphingolipids (Gorai et al. 2012; Vacirca et al. 2012), both plasma membrane preparations were treated with the mild non-ionic detergent digitonin (Nielsen et al. 2005), which forms an equimolar complex with cholesterol. Moreover, digitonin was chosen being widely used to extract F 0 F 1 complexes from the inner mitochondrial membrane (Wittig et al. 2006), because it maintains the ATP synthase oligomeric forms (Giorgio et al. 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Over the past few years, several reports have described the presence of F0F1 ATP synthase subunits at the surface of hepatocytes, where the hydrolytic activity of F1 sector faces outside and triggers HDL endocytosis. An intriguing question is whether the ectopic enzyme has same subunit composition and molecular mass as that of the mitochondrial ATP synthase. Also due to the polar nature of hepatocytes, the enzyme may be localized to a particular cell boundary. Using different methods to prepare rat liver plasma membranes, which have been subjected to digitonin extraction, hr CN PAGE, immunoblotting, and mass spectrometry analysis, we demonstrate the presence of ecto-F0F1 complexes which have a similar molecular weight to the monomeric form of the mitochondrial complexes, containing both nuclear and mitochondrially-encoded subunits. This finding makes it unlikely that the enzyme assembles on the plasma membranes, but suggest it to be transported whole after being assembled in mitochondria by still unknown pathways. Moreover, the plasma membrane preparation enriched in basolateral proteins contains much higher amounts of complete and active F0F1 complexes, consistent with their specific function to modulate the HDL uptake on hepatocyte surface.
    Full-text · Article · Aug 2013 · Journal of Bioenergetics
  • Source
    • "Like CRMP2, ATP synthase alpha was also found to be colocalized with the NFT, suggesting that the oxidation of these proteins plays an important role in the progression and pathogenesis of AD [168]. A recent study by Vacirca et al. [169] [170] reported the presence of autoantibodies to ecto-F1- ATPase (ASabs) in sera and cerebrospinal fluids from patients with AD. Further, these researchers also showed that ASabs can increase cellular uptake of high density lipoprotein (HDL) via a mechanism involving the prototypical function of ecto-F1-ATPase. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Lipid peroxidation involves a cascade of reactions in which production of free radicals occurs selectively in the lipid components of cellular membranes. Polyunsaturated fatty acids easily undergo lipid peroxidation chain reactions, which, in turn, lead to the formation of highly reactive electrophilic aldehydes. Among these, the most abundant aldehydes are 4-hydroxy-2-nonenal (HNE) and malondialdehyde, while acrolein is the most reactive. Proteins are susceptible to posttranslational modifications caused by aldehydes binding covalently to specific amino acid residues, in a process called Michael adduction, and these types of protein adducts, if not efficiently removed, may be, and generally are, dangerous for cellular homeostasis. In the present review, we focused the discussion on the selective proteins that are identified, by redox proteomics, as selective targets of HNE modification during the progression and pathogenesis of Alzheimer disease (AD). By comparing results obtained at different stages of the AD, it may be possible to identify key biochemical pathways involved and ideally identify therapeutic targets to prevent, delay, or treat AD.
    Preview · Article · Oct 2012 · Free Radical Biology and Medicine
  • Source
    • "An indirect immunofluorescence assay was developed on SH-SY5Y cells and primary hippocampal neurons, as previously described [44]. Cells were fixed with 4% PFA in PBS for 30 min at 4°C or permeabilized with acetone/methanol 1/1 (v/v) for 10 min at 4°C and then were incubated for 30 min at 25°C in the blocking buffer (2% BSA in PBS, containing 5% glycerol and 0.2% Tween 20). "
    [Show abstract] [Hide abstract]
    ABSTRACT: In addition to the classical nuclear estrogen receptor, the expression of non-nuclear estrogen receptors localized to the cell surface membrane (mER) has recently been demonstrated. Estrogen and its receptors have been implicated in the development or progression of numerous neurodegenerative disorders. Furthermore, the pathogenesis of these diseases has been associated with disturbances of two key cellular programs: apoptosis and autophagy. An excess of apoptosis or a defect in autophagy has been implicated in neurodegeneration. The aim of this study was to clarify the role of ER in determining neuronal cell fate and the possible implication of these receptors in regulating either apoptosis or autophagy. The human neuronal cell line SH-SY5Y and mouse neuronal cells in primary culture were thus exposed to chronic minimal peroxide treatment (CMP), a form of subcytotoxic minimal chronic stress previously that mimics multiple aspects of long-term cell stress and represents a limited molecular proxy for neurodegenerative processes. We actually found that either E2 or E2-bovine serum albumin construct (E2BSA, i.e. a non-permeant form of E2) was capable of modulating intracellular cell signals and regulating cell survival and death. In particular, under CMP, the up-regulation of mERα, but not mERβ, was associated with functional signals (ERK phosphorylation and p38 dephosphorylation) compatible with autophagic cytoprotection triggering and leading to cell survival. The mERα trafficking appeared to be independent of the microfilament system cytoskeletal network but was seemingly associated with microtubular apparatus network, i.e., to MAP2 molecular chaperone. Importantly, antioxidant treatments, administration of siRNA to ERα, or the presence of antagonist of ERα hindered these events. These results support that the surface expression of mERα plays a pivotal role in determining cell fate, and that ligand-induced activation of mER signalling exerts a powerful cell-survival signal. These results shed new light on the pathogenetic mechanisms leading to neuronal cell degeneration.
    Full-text · Article · Jul 2012 · PLoS ONE
Show more