Identification of a peptide recognizing cerebrovascular changes in mouse models of Alzheimer\u2019s disease

Aman P Mann,Stuart A Lipton,Tambet Teesalu,Erkki Ruoslahti,Tarmo Mölder,Gary B Braun,Rajesh Ambasudhan,Sazid Hussain,Kadri Toome,Pablo Scodeller

doi:10.1038/s41467-017-01096-0

Abstract

Cerebrovascular changes occur in Alzheimer’s disease (AD). Using in vivo phage display, we searched for molecular markers of the neurovascular unit, including endothelial cells and astrocytes, in mouse models of AD. We identified a cyclic peptide, CDAGRKQKC (DAG), that accumulates in the hippocampus of hAPP-J20 mice at different ages. Intravenously injected DAG peptide homes to neurovascular unit endothelial cells and to reactive astrocytes in mouse models of AD. We identified connective tissue growth factor (CTGF), a matricellular protein that is highly expressed in the brain of individuals with AD and in mouse models, as the target of the DAG peptide. We also showed that exogenously delivered DAG homes to the brain in mouse models of glioblastoma, traumatic brain injury, and Parkinson’s disease. DAG may potentially be used as a tool to enhance delivery of therapeutics and imaging agents to sites of vascular changes and astrogliosis in diseases associated with neuroinflammation.

Highlights

Cerebrovascular changes occur in Alzheimer’s disease (AD)
Given the changes reported in the neurovascular unit in AD, we conducted in vivo phage display to identify peptides that recognize molecular changes associated with AD pathogenesis, and enable targeting of such sites from systemic administration
DAG, selectively recognizes a subset of astrocytes that are activated in AD starting at an early stage of the disease

Summary

Introduction

Cerebrovascular changes occur in Alzheimer’s disease (AD). Using in vivo phage display, we searched for molecular markers of the neurovascular unit, including endothelial cells and astrocytes, in mouse models of AD. A control peptide for DAG, with the same overall structure and charge (+2) (sequence: CRKQGEAKC) showed essentially no homing to the hippocampus of hAPP-J20 mice of the same age (Fig. 1d, bottom panel), confirming DAG specificity for the hAPP-J20 brain.

Results

Conclusion