DOI: 10.1002/cbic.201000237 Controlling Amyloid-b Peptide(1–42) Oligomerization and Toxicity by Fluorinated Nanoparticles Ana M. Saraiva ,* [a, b] Isabel Cardoso , [c, d] M. Carmo Pereira, [b] Manuel A. N. Coelho, [b] Maria Jo¼o Saraiva, [c] Helmuth Mçhwald, [a] and Gerald Brezesinski* [a] Introduction Alzheimer’s disease (AD) is the most common cause of demen- tia in the elderly and is characterized by the extracellular accu- mulation of senile plaques, the intracellular appearance of neu- rofibrillary tangles, and neuronal loss. Evidence from genetic and animal models have established a causative role of the amyloid-b peptide (Ab) in the disease. [1–4] In AD brains, the peptide is found in a fibrillar form organized in a b-sheet struc- ture, being the main constituent of the plaque deposits. [5] Ab is a 4 kDa peptide, generated by endoproteolytic cleavage of the amyloid precursor protein (APP) by two proteases, b- and g-secretase. APP is a ubiquitous glycosylated transmembrane protein produced in several isoforms ranging from 695 to 770 amino-acid residues. The shorter APP695, the most abundant form in the brain, [6] is suggested to have biological activities that affect neuronal development and function. [7] Ab most common isoforms are 40 and 42 residues long, differing by two hydrophobic residues at the C terminus. The N terminus is rich in charged residues, and there are two hydrophobic stretches, Leu17–Ala21 and Ala30–Ala42, believed to be the key for oligomerization. [8, 9] There is a number of naturally oc- curring alloforms with substitutions usually in or near the cen- tral hydrophobic cluster (CHC). In each instance, the disease has variations in onset and symptoms. [10, 11] In spite of the small structural difference, the peptides display distinct biological, biophysical, and clinical behavior. Although under normal con- ditions of APP processing Ab40 is about ten times more abun- dant, Ab42 is the predominant species in plaques. [12, 13] Ab42 has been shown to aggregate more rapidly than Ab40 [14, 15] and to have enhanced neurotoxicity. [16, 17] Recent debate has focused on whether amyloid fibrils or soluble oligomers of Ab are the main neurotoxic species that contribute to neurodegeneration and dementia. [18] Concerning the former, the most frequent objection is the weak correlation between the amount of amyloid deposits detected by post- mortem neuropathological analysis and the degree of cogni- tive impairment experienced by patients in life. [19] Because soluble Ab levels correlate better with the severity of AD than insoluble Ab, [20] there is growing evidence that soluble oligo- meric forms might be a critical component in AD pathology rather than insoluble fibrils. [21, 22] The so-called ADDLs [23] or pro- tofibrils [24] cause subtle injury to cultured neurons, and injec- tion of Ab oligomers in rats can inhibit long-term potentiation in the hippocampus, which is required for memory forma- tion. [25] It was suggested that these oligomeric structures induce toxicity through a mechanism related to the folded structure rather than sequence. [17, 26] Further evidence was ob- tained when antibodies specific to Ab oligomers were shown to inhibit toxicity not only of Ab oligomers but of several other protein oligomers as well. [22] The amyloid-b peptide (Ab) is a major fibrillar component of neuritic plaques in Alzheimer’s disease brains and is related to the pathogenesis of the disease. Soluble oligomers that pre- cede fibril formation have been proposed as the main neuro- toxic species that contributes to neurodegeneration and de- mentia. We hypothesize that oligomerization and cytotoxicity can be repressed by nanoparticles (NPs) that induce conforma- tional changes in Ab42. We show here that fluorinated and hy- drogenated NPs with different abilities to change Ab42 confor- mation influence oligomerization as assessed by atomic force microscopy, immunoblot and SDS-PAGE. Fluorinated NPs, which promote an increase in a-helical content, exert an antio- ligomeric effect, whereas hydrogenated analogues do not and lead to aggregation. Cytotoxicity assays confirmed our hypoth- esis by indicating that the conformational conversion of Ab42 into an a-helical-enriched secondary structure also has anti- apoptotic activity, thereby increasing the viability of cells treat- ed with oligomeric species. [a] Dr. A. M. Saraiva , Prof. H. Mçhwald, Prof. G. Brezesinski Interfaces Department, Max Planck Institute of Colloids and Interfaces Wissenschaftspark Golm 14476 Potsdam (Germany) Fax: (+ 49) 331-567-9222 E-mail : saraiva@mpikg.mpg.de brezesinski@mpikg.mpg.de [b] Dr. A. M. Saraiva , Prof. M. C. Pereira, Prof. M. A. N. Coelho LEPAE, Department of Chemical Engineering Faculty of Engineering, University of Porto Rua Dr. Roberto Frias, 4200-465 Porto (Portugal) [c] Dr. I. Cardoso , Prof. M. J. Saraiva Molecular Neurobiology Unit Instituto de Biologia Molecular e Celular Rua do Campo Alegre 823, 4150-180 Porto (Portugal) [d] Dr. I. Cardoso School of Allied Health Science, Instituto PolitØcnico do Porto Rua Valente Perfeito, 322, 4400-330, Vila Nova de Gaia (Portugal) ChemBioChem 2010, 11, 1905 – 1913  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1905