Naturally occurring antibodies against ASC are reduced in Alzheimer's Disease and alleviate AD-type pathology in APP/PS1 mice.

Abstract

The disruption or increased permeability of the blood-brain barrier (BBB) results in dysregulated autoantibody profiles in Alzheimer's disease (AD) patients. Naturally occurring antibodies against ASC (NAbs-ASC), which are present in human blood, can block the ability of ASC specks to seed Aβ aggregation. However, the characteristics and functions of NAbs-ASC in AD remain unclear. In this study, we found that plasma levels of NAbs-ASC were reduced in AD patients and showed negative correlation with the severity of cognitive impairment and with plasma Aβ42/40 ratios. NAbs-ASC treatment reduced Aβ production and attenuated Aβ-induced cytotoxicity in AD cell models. Furthermore, passive immunization with NAbs-ASC or active immunization with ASC peptides improved cognitive function, attenuated Aβ deposition, reduced Tau phosphorylation, inhibited neuroinflammation and apoptosis, and improved synaptic plasticity in APP/PS1 mice. These findings support that NAbs-ASC maybe important physiological protective factors for AD, and that immunotherapy targeting ASC may be a potential therapeutic intervention for the disease.