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 proxies 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. KeywordsAmyloid-β; free radicals; oxidative stress; Alzheimer's disease; hydrazide; hydralazine; 4-hydroxy-2-nonenal Amyloid β protein (Aβ), which misfolds and accumulates in Alzheimer's disease (AD) brains, is central to the "amyloid hypothesis" where Aβ causes AD pathology [1,2]. This toxicity is in part due to increased oxidative damage [3][4][5][6][7][8] and the toxicity of oligomeric species of Aβ [9]. Indeed, Aβ may play a direct role in this oxidative damage as it directly oxidizes many substrates, including lipids [10][11][12][13][14][15]. Additionally, amyloid plaques, of which Aβ is the major component [16,17] and contain transition metals [18][19][20][21][22][23][24] as well as are competent for generating oxidative stress [18,25,26]. The oxidation products generated, such as H 2 O 2 and reactive lipid oxidation products such as 4-hydroxy-2-nonenal (HNE), are likely mediators of toxicity in this disease. Identification of compounds that can prevent these two pathological features of AD, oxidative damage and protein misfolding, could provide the basis for future drugs for AD. Hydralazine was selected as it is an excellent scavenger of reactive lipid oxidation products, such as acrolein and HNE, and also prevents the lipid modification and crosslinking of proteins [27][28][29][30][31][32][33][34][35]. In addition to reducing reactive oxygen species and lipid peroxidation, hydralaz...