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(American Journal of Pathology. 2004;165:937-948.)
© 2004 American Society for Investigative Pathology

A Synthetic Peptide Blocking the Apolipoprotein E/ß-Amyloid Binding Mitigates ß-Amyloid Toxicity and Fibril Formation in Vitro and Reduces ß-Amyloid Plaques in Transgenic Mice

Marcin Sadowski*, Joanna Pankiewicz*, Henrieta Scholtzova*, James A. Ripellino*, Yongsheng Li*, Stephen D. Schmidt{dagger}, Paul M. Mathews{dagger}, John D. Fryer{ddagger}, David M. Holtzman{ddagger}, Einar M. Sigurdsson§ and Thomas Wisniewski*§

From the Departments of Neurology,* Psychiatry§ and Pathology, New York University School of Medicine, New York, New York; Nathan S. Kline Institute,{dagger} New York University, Orangeburg, New York; and the Departments of Neurology, Molecular Biology, and Pharmacology,{ddagger} Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, Missouri

Alzheimer’s disease (AD) is associated with accumulation of ß-amyloid (Aß). A major genetic risk factor for sporadic AD is inheritance of the apolipoprotein (apo) E4 allele. ApoE can act as a pathological chaperone of Aß, promoting its conformational transformation from soluble Aß into toxic aggregates. We determined if blocking the apoE/Aß interaction reduces Aß load in transgenic (Tg) AD mice. The binding site of apoE on Aß corresponds to residues 12 to 28. To block binding, we synthesized a peptide containing these residues, but substituted valine at position 18 to proline (Aß12–28P). This changed the peptide’s properties, making it non-fibrillogenic and non-toxic. Aß12–28P competitively blocks binding of full-length Aß to apoE (IC50 = 36.7 nmol). Furthermore, Aß12–28P reduces Aß fibrillogenesis in the presence of apoE, and Aß/apoE toxicity in cell culture. Aß12–28P is blood-brain barrier-permeable and in AD Tg mice inhibits Aß deposition. Tg mice treated with Aß12–28P for 1 month had a 63.3% reduction in Aß load in the cortex (P = 0.0043) and a 59.5% (P = 0.0087) reduction in the hippocampus comparing to age-matched control Tg mice. Antibodies against Aß were not detected in sera of treated mice; therefore the observed therapeutic effect of Aß12–28P cannot be attributed to an antibody clearance response. Our experiments demonstrate that compounds blocking the interaction between Aß and its pathological chaperones may be beneficial for treatment of ß-amyloid deposition in AD.




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