Hydralazine modifies Aβ fibril formation and prevents modification by lipids in vitro

Mukesh Maheshwari, Jessica K. Roberts, Brent Desutter, Karen T. Duong, Joseph Tingling, Janelle N. Fawver, Hayley E. Schall, Michael Kahle, Ian V.J. Murray

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Lipid oxidative damage and amyloid β (Aβ) misfolding contribute to Alzheimer's disease (AD) pathology. Thus, the prevention of oxidative damage and Aβ misfolding are attractive targets for drug discovery. At present, no AD drugs approved by the Food and Drug Administration (FDA) prevent or halt disease progression. Hydralazine, a smooth muscle relaxant, is a potential drug candidate for AD drug therapy as it reduces Aβ production and prevents oxidative damage via its antioxidant hydrazide group. We evaluated the efficacy of hydralazine, and related hydrazides, in reducing (1) Aβ misfolding and (2) Aβ protein modification by the reactive lipid 4-hydroxy-2-nonenal (HNE) using transmission electron microscopy and Western blotting. While hydralazine did not prevent Aβ aggregation as measured using the protease protection assay, there were more oligomeric species observed by electron microscopy. Hydralazine prevented lipid modification of Aβ, and Aβ was used as a proxy for classes of proteins which either misfold or are modified by HNE. All of the other hydrazides prevented lipid modification of Aβ and also did not prevent Aβ aggregation. Surprisingly, a few of the compounds, carbazochrome and niclosamide, appeared to augment Aβ formation. Thus, hydrazides reduced lipid oxidative damage, and hydralazine additionally reduced Aβ misfolding. While hydralazine would require specific chemical modifications for use as an AD therapeutic itself (to improve blood brain barrier permeability, reduce vasoactive side effects, and optimization for amyloid inhibition), this study suggests its potential merit for further AD drug development.

Original languageEnglish (US)
Pages (from-to)10371-10380
Number of pages10
JournalBiochemistry
Volume49
Issue number49
DOIs
StatePublished - Dec 14 2010
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry

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