Naturally Occurring Autoantibodies against β-Amyloid: Investigating Their Role in Transgenic Animal andIn VitroModels of Alzheimer's Disease (original) (raw)
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Journal of Neuroscience, 2011
Alzheimer's disease (AD) is a neurodegenerative disorder primarily affecting regions of the brain responsible for higher cognitive functions. Immunization against -amyloid (A) in animal models of AD has been shown to be effective on the molecular level but also on the behavioral level. Recently, we reported naturally occurring autoantibodies against A (NAbs-A) being reduced in Alzheimer's disease patients. Here, we further investigated their physiological role: in epitope mapping studies, NAbs-A recognized the mid-/Cterminal end of A and preferentially bound to oligomers but failed to bind to monomers/fibrils. NAbs-A were able to interfere with A peptide toxicity, but NAbs-A did not readily clear senile plaques although early fleecy-like plaques were reduced. Administration of NAbs-A in transgenic mice improved the object location memory significantly, almost reaching performance levels of wild-type control mice. These findings suggest a novel physiological mechanism involving NAbs-A to dispose of proteins or peptides that are prone to forming toxic aggregates.
Translational psychiatry, 2013
There is evidence that naturally occurring antibodies directed against Aβ (nAbs-Aβ) have a role in Aβ-metabolism and Aβ-clearance. The presence of nAbs-Aβ leads to a reduction in amyloid fibrillation and thus a reduction in their toxicity. We investigated the effects of nAbs-Aβ in respect to oligomerization and used the Tg2576 transgenic mouse model in order to investigate the rapid effect with a single-dose (24 h) on oligomer breakdown and cytokine secretion along with immunohistochemical characterization of synaptic plasticity. nAbs-Aβ were able to reduce toxic oligomer concentration with an increase in Aβ-monomers. Cytokine secretion was significantly reduced. Synaptic plasticity was also improved after administration of nAbs. Finally, single treatment lead to a significant improvement in cognition. This study demonstrates the efficacy of nAbs-Aβ and presents evidence that several hallmarks of the disease are targeted by nAbs-Aβ.
Beta-amyloid auto-antibodies are reduced in Alzheimer's disease
Journal of Neuroimmunology, 2014
Accumulation and cytotoxicity of amyloid beta (Aβ) are understood as the major cause of Alzheimer's disease (AD). There is evidence that naturally occurring antibodies against amyloid beta (Aβ) protein play a role in Aβ-clearance, and such a mechanism appears to be impaired in AD. In the present study, the anti-Aβ antibodies in the serum from individuals with and without late onset AD were measured using ELISA and dot-blot methods. Aβ auto-antibodies in serum were mainly targeted to Aβ1-15 epitope and its titer was significantly lower in AD patients than elderly non-AD controls (NC). The dot-blot analysis further demonstrated that auto-antibodies against fibrillar Aβ42, Aβ1-15 and Aβ16-30 epitopes were all in a lower level in AD than in NC. The isotypes of the auto-antibodies were mainly non-inflammatory IgG2 type. We also analyzed the relationship of auto-Aβ antibodies levels with the genotypes of Apolipoprotein E (ApoE) and ANKK1/DRD2 gene.
Journal of Alzheimer's disease : JAD, 2011
Previous studies have reported immunoglobulin-positive neurons in Alzheimer's disease (AD) brains, an observation indicative of blood-brain barrier (BBB) breakdown. Recently, we demonstrated the nearly ubiquitous presence of brain-reactive autoantibodies in human sera. The significance of these observations to AD pathology is unknown. Here, we show that IgG-immunopositive neurons are abundant in brain regions exhibiting AD pathology, including intraneuronal amyloid-β(42) (Aβ(42)) and amyloid plaques, and confirm by western analysis that brain-reactive autoantibodies are nearly ubiquitous in human serum. To investigate a possible interrelationship between neuronal antibody binding and Aβ pathology, we tested the effects of human serum autoantibodies on the intraneuronal deposition of soluble Aβ(42) peptide in adult mouse neurons in vitro (organotypic brain slice cultures). Binding of human autoantibodies to mouse neurons dramatically increased the rate and extent of intraneuronal...
Journal of Alzheimer's Disease
Blood-brain barrier (BBB) permeability is a recognized early feature of Alzheimer's disease (AD). In the present study, we examined consequences of increased BBB permeability on the development of AD-related pathology by tracking selected leaked plasma components and their interactions with neurons in vivo and in vitro. Histological sections of cortical regions of postmortem AD brains were immunostained to determine the distribution of amyloid- 1-42 (A 42), cathepsin D, IgG, GluR2/3, and alpha7 nicotinic acetylcholine receptor (␣7nAChR). Results revealed that chronic IgG binding to pyramidal neurons coincided with internalization of A 42, IgG, GluR2/3, and ␣7nAChR as well as lysosomal compartment expansion in these cells in regions of AD pathology. To test possible mechanistic interrelationships of these phenomena, we exposed differentiated SH-SY5Y neuroblastoma cells to exogenous, soluble A 42 peptide and serum from AD and control subjects. The rate and extent of A 42 internalization in these cells was enhanced by serum containing neuron-binding IgG autoantibodies. This was confirmed by treating cells with individual antibodies specific for ␣7nAChR, purified IgG from AD or non-AD sera, and sera devoid of IgG, in the presence of 100 nM A 42. Initial co-localization of IgG, ␣7nAChR, and A 42 was temporally and spatially linked to early endosomes (Rab11) and later to lysosomes (LAMP-1). A 42 internalization was attenuated by treatment with monovalent F(ab) antibody fragments generated from purified IgG from AD serum and then