Brain-reactive autoantibodies prevalent in human sera increase intraneuronal amyloid-β(1-42) deposition (original) (raw)
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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
PLoS ONE, 2013
Recent studies have suggested a protective role of physiological b-amyloid autoantibodies (Ab-autoantibodies) in Alzheimer's disease (AD). However, the determination of both free and dissociated Ab-autoantibodies in serum hitherto has yielded inconsistent results regarding their function and possible biomarker value. Here we report the application of a new sandwich enzyme-linked immunosorbent assay (ELISA) for the determination of antigen-bound Ab-autoantibodies (intact Ab-IgG immune complexes) in serum and cerebrospinal fluid (CSF) of a total number of 112 AD patients and age-and gender-matched control subjects. Both serum and CSF levels of Ab-IgG immune complexes were found to be significantly higher in AD patients compared to control subjects. Moreover, the levels of Ab-IgG complexes were negatively correlated with the cognitive status across the groups, increasing with declining cognitive test performance of the subjects. Our results suggest a contribution of IgG-type autoantibodies to Ab clearance in vivo and an increased immune response in AD, which may be associated with deficient Ab-IgG removal. These findings may contribute to elucidating the role of Abautoantibodies in AD pathophysiology and their potential application in AD diagnosis. Citation: Maftei M, Thurm F, Schnack C, Tumani H, Otto M, et al. (2013) Increased Levels of Antigen-Bound b-Amyloid Autoantibodies in Serum and Cerebrospinal Fluid of Alzheimer's Disease Patients. PLoS ONE 8(7): e68996.
Biological Psychiatry, 2005
Background: Autoantibodies against amyloid  (A) peptide found in patients with Alzheimer's disease (AD) also occur naturally in the general population independently of the cognitive status. Methods: We compared serum A 1-42 autoantibody levels (A 1-42-AL) of 96 AD patients and 30 healthy elderly control subjects (HC), assessing their diagnostic value for AD with a newly developed immunoprecipitation assay with radiolabeled A 1-42 peptide. Results: We found a highly significant decrease of A 1-42-AL in AD patients (p ϭ .001) independently of age, cognitive status, and apolipoprotein Eε4 carrier status. Amyloid  1-42 autoantibody levels were correlated with gender in AD, with a higher level occurring in women. When A 1-42 autoantibody sensitivity (specificity) was set Ͼ80%, specificity (sensitivity) was below 50% to correctly allocate patients and healthy control subjects. Conclusions: Our data indicate a potentially pathophysiologic decrease of serum A 1-42 antibodies in AD. Amyloid  1-42 antibodies in the serum alone, however, seem not to be useful as a diagnostic marker of AD.
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.
The 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 β-amyloid (Aβ) 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 Aβ (NAbs–Aβ) being reduced in Alzheimer's disease patients. Here, we further investigated their physiological role: in epitope mapping studies, NAbs–Aβ recognized the mid-/C-terminal end of Aβ and preferentially bound to oligomers but failed to bind to monomers/fibrils. NAbs–Aβ were able to interfere with Aβ peptide toxicity, but NAbs–Aβ did not readily clear senile plaques although early fleecy-like plaques were reduced. Administration of NAbs–Aβ in transgenic mice improved the object location memory significantly, almost reaching performance levels of wild-type control mice. These findings suggest a novel physiological mechan...
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.
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.
The Pathology of Alzheimer Disease Elicits an In Vivo Immunological Response
American Journal of Immunology, 2007
The mechanism(s) responsible for the loss of neurons that characterizes Alzheimer disease is incompletely understood. Nonetheless, there is considerable evidence suggestive of immune abnormalities coupled to alterations in blood-brain barrier permeability that likely play a key role in both the etiology and progression of the disease. To examine these issues further, this study was designed to examine the presence of human antibodies within hippocampal regions of both diseased and normal brains. Specifically, using antibodies directed against either human lambda () or kappa () subunits of human IgG, we examined the amount and localization of endogenous human antibodies within the brain. In cases of Alzheimer disease, but not in age-matched controls, we found human antibodies associated with pyramidal neurons and dystrophic neurites surrounding amyloid plaquespathological structures that characterize the disease. Since such human immunoglobulins likely originate in the vasculature, we also examined cases of cerebral amyloid angiopathy to further explore the importance of blood-brain barrier breaches and found high levels of antibodies associated with many blood vessels as well as pyramidal neurons. Taken together, these findings strengthen the notion that alterations in blood brain barrier permeability in both Alzheimer disease and cerebral amyloid angiopathy leads to the accumulation of antibodies that then may contribute to the inflammatory cascade within the brain.