A synthetic peptide blocking the apolipoprotein E/β-amyloid binding mitigates β-amyloid toxicity and fibril formation in vitro and reduces β-amyloid plaques in transgenic mice

Marcin Sadowski, Joanna Pankiewicz, Henrieta Scholtzova, James A. Ripellino, Yongsheng Li, Stephen D. Schmidt, Paul M. Mathews, John D. Fryer, David M. Holtzman, Einar M. Sigurdsson, Thomas Wisniewski

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118 Scopus citations

Abstract

Alzheimer's disease (AD) is associated with accumulation of β-amyloid (Aβ). A major genetic risk factor for sporadic AD is inheritance of the apolipoprotein (apo) E4 allele. ApoE can act as a pathological chaperone of Aβ, promoting its conformational transformation from soluble Aβ into toxic aggregates. We determined if blocking the apoE/Aβ interaction reduces Aβ load in transgenic (Tg) AD mice. The binding site of apoE on Aβ corresponds to residues 12 to 28. To block binding, we synthesized a peptide containing these residues, but substituted valine at position 18 to proline (Aβl2-28P). This changed the peptide's properties, making it non-fibrillogenic and non-toxic. Aβl2-28P competitively blocks binding of full-length Aβ to apoE (IC50 = 36.7 nmol). Furthermore, Aβl2-28P reduces Aβ fibrillogenesis in the presence of apoE, and Aβ/apoE toxicity in cell culture. Aβl2-28P is blood-brain barrier-permeable and in AD Tg mice inhibits Aβ deposition. Tg mice treated with Aβ12-28P for 1 month had a 63-3% reduction in Aβ 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 Aβ were not detected in sera of treated mice; therefore the observed therapeutic effect of Aβl2-28P cannot be attributed to an antibody clearance response. Our experiments demonstrate that compounds blocking the interaction between Aβ and its pathological chaperons may be beneficial for treatment of β-amyloid deposition in AD.

Original languageEnglish (US)
Pages (from-to)937-948
Number of pages12
JournalAmerican Journal of Pathology
Volume165
Issue number3
DOIs
StatePublished - Sep 2004

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Sadowski, M., Pankiewicz, J., Scholtzova, H., Ripellino, J. A., Li, Y., Schmidt, S. D., Mathews, P. M., Fryer, J. D., Holtzman, D. M., Sigurdsson, E. M., & Wisniewski, T. (2004). A synthetic peptide blocking the apolipoprotein E/β-amyloid binding mitigates β-amyloid toxicity and fibril formation in vitro and reduces β-amyloid plaques in transgenic mice. American Journal of Pathology, 165(3), 937-948. https://doi.org/10.1016/S0002-9440(10)63355-X