Naturally Occurring Autoantibodies against -Amyloid: Investigating Their Role in Transgenic Animal and In Vitro Models of Alzheimer's Disease

Department of Neurology, Philipps University Marburg, D-35043 Marburg, Germany.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 04/2011; 31(15):5847-54. DOI: 10.1523/JNEUROSCI.4401-10.2011
Source: PubMed


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 mechanism involving NAbs-Aβ to dispose of proteins or peptides that are prone to forming toxic aggregates.

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    • "The function of anti-A antibodies is not understood but they have been implied to interfere with A toxicity and the oligomerization and fibrillization of A [1] [14] [16] [18] [19]. As a therapeutic approach, intravenous infusion of polyvalent IgG antibodies from healthy individuals (IVIG), proposed to contain anti- A antibodies, has been studied in AD with positive effects on mouse behavior [14] [20] and AD cognition [21] [22] [23]. Nevertheless, to this date, clinical trials have failed to show any positive treatment effects of IVIG in AD [24] [25]. "
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    • "These drugs differ in their levels of anti-Aβ antibodies [10-12]. IVIG has been shown in vitro to disaggregate preformed Aβ fibrils, promote Aβ phagocytic removal [36], protect against Aβ neurotoxicity [35,37], and prevent formation of Aβ soluble oligomers [11]. But studies in mouse models of AD have produced conflicting results as to whether IVIG products can reduce brain Aβ. "
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