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

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.