Neuroserpin Binds Aβ and Is a Neuroprotective Component of Amyloid Plaques in Alzheimer Disease

Kerri J Kinghorn,Damian C Crowther,Lynda K Sharp,Charlotte Nerelius,Richard L Davis,Howard T Chang,Clare Green,David C Gubb,Jan Johansson,David A Lomas

doi:10.1074/jbc.m600690200

Abstract

Alzheimer disease is characterized by extracellular plaques composed of Abeta peptides. We show here that these plaques also contain the serine protease inhibitor neuroserpin and that neuroserpin forms a 1:1 binary complex with the N-terminal or middle parts of the Abeta(1-42) peptide. This complex inactivates neuroserpin as an inhibitor of tissue plasminogen activator and blocks the loop-sheet polymerization process that is characteristic of members of the serpin superfamily. In contrast neuroserpin accelerates the aggregation of Abeta(1-42) with the resulting species having an appearance that is distinct from the mature amyloid fibril. Neuroserpin reduces the cytotoxicity of Abeta(1-42) when assessed using standard cell assays, and the interaction has been confirmed in vivo in novel Drosophila models of disease. Taken together, these data show that neuroserpin interacts with Abeta(1-42) to form off-pathway non-toxic oligomers and so protects neurons in Alzheimer disease.

Highlights

Dysfunction and death (4 – 6) has emphasized the importance of understanding the pathways and kinetics of A␤ aggregation
The role of these proteins is underscored by the finding that the E4 polymorphism of apolipoprotein E is the most powerful genetic risk factor for the development of sporadic Alzheimer disease [9, 10], most likely because it accelerates the deposition of A␤ in the brain [11,12,13]. ␣1-Antichymotrypsin is found in the majority of senile plaques [8], with cerebrospinal fluid concentrations being consistently raised in patients with Alzheimer disease [14]
Wild-type neuroserpin is expressed throughout the nervous system and inhibits the serine protease tissue plasminogen activator4 [19, 22, 23]. tPA plays a critical role in neural development, synaptic plasticity, and memory [24], and its levels rise in animal models of both stroke and epilepsy [25,26,27]

Summary

Introduction

Dysfunction and death (4 – 6) has emphasized the importance of understanding the pathways and kinetics of A␤ aggregation. A␤1–42 Abolishes the Protease Inhibitory Activity of Neuroserpin by the Formation of a 1:1 Molar Complex—To determine whether the localization of neuroserpin to ␤ amyloid plaques represents a specific interaction between the serpin and the A␤ peptide, we investigated the functional consequences of co-incubating pure solutions of protein and peptide.

Results

Conclusion