A novel Aβ-fibrinogen interaction inhibitor rescues altered thrombosis and cognitive decline in Alzheimer's disease mice

  • J Exp Med. 2014 Jun 2;211(6):1049-62. doi: 10.1084/jem.20131751.
Hyung Jin Ahn  1 ,  J Fraser Glickman  1 ,  Ka Lai Poon  1 ,  Daria Zamolodchikov  1 ,  Odella C Jno-Charles  1 ,  Erin H Norris  1 ,  Sidney Strickland  2
Affiliations
  • 1. Laboratory of Neurobiology and Genetics and High Throughput Screening Resource Center, The Rockefeller University, New York, NY 10065.
  • 2. Laboratory of Neurobiology and Genetics and High Throughput Screening Resource Center, The Rockefeller University, New York, NY 10065 [email protected].
PMID: 24821909 DOI: 10.1084/jem.20131751
Abstract

Many Alzheimer's disease (AD) patients suffer from cerebrovascular abnormalities such as altered cerebral blood flow and cerebral microinfarcts. Recently, fibrinogen has been identified as a strong cerebrovascular risk factor in AD, as it specifically binds to β-amyloid (Aβ), thereby altering fibrin clot structure and delaying clot degradation. To determine if the Aβ-fibrinogen interaction could be targeted as a potential new treatment for AD, we designed a high-throughput screen and identified RU-505 as an effective inhibitor of the Aβ-fibrinogen interaction. RU-505 restored Aβ-induced altered fibrin clot formation and degradation in vitro and inhibited vessel occlusion in AD transgenic mice. Furthermore, long-term treatment of RU-505 significantly reduced vascular amyloid deposition and microgliosis in the cortex and improved cognitive impairment in mouse models of AD. Our studies suggest that inhibitors targeting the Aβ-fibrinogen interaction show promise as therapy for treating AD.

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