Beta-Amyloid Monomers Are Neuroprotective(659 views) Giuffrida ML, Caraci F, Pignataro B, Cataldo S, De Bona P, Bruno V, Molinaro G, Pappalardo G, Messina A, Palmigiano A, Garozzo D, Nicoletti F, Rizzarelli E, Copani A
Department of Pharmaceutical Sciences, University of Catania, Viale Andrea Doria 6, 95125 Catania, Italy
Department of Physical-Chemistry, University of Palermo, Palermo 90100, Italy
Department of Chemical Sciences, University of Catania, Catania 95125, Italy
Department of Human Physiology and Pharmacology, University of Rome La Sapienza, Rome 00185, Italy
Istituto Neurologico Mediterraneo, Neuromed., Pozzilli 86077, Italy
Institute of Biostructure and Bioimaging, National Research Council, Catania 95125, Italy
Istituto di Chimica e Tecnologia dei Polimeri-Consiglio Nazionale Delle Ricerche, Catania 95126, Italy
Istituto Nazionale Biostrutture e Biosistemi, Rome 00136, Italy
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Rodziewicz-Motowidło, S., Juszczyk, P., Sikorska, E., Spodzieja, M., Kołodziejczyk, A.S., The Arctic mutation alters helix length and type in the 11-28 beta-amyloid peptide monomer-CD, NMR and MD studies in an SDS micelle (2008) J Struct Biol, , Advance online publication. Retrieved July 24, 2008. doi:10.1016/j.jsb. 2008.07.010
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Vlahos, C.J., Matter, W.F., Hui, K.Y., Brown, R.F., A specific inhibitor of phosphyatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002) (1994) Journal of Biological Chemistry, 269 (7), pp. 5241-5248
Walsh, D.M., Selkoe, D.J., A beta oligomers - A decade of discovery (2007) J Neurochem, 101, pp. 1172-1184
Walsh, D.M., Klyubin, I., Fadeeva, J.V., Cullen, W.K., Anwyl, R., Wolfe, M.S., Rowan, M.J., Selkoe, D.J., Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo (2002) Nature, 416 (6880), pp. 535-539. , DOI 10.1038/416535a
Rodziewicz-Motowidlo, S., Juszczyk, P., Sikorska, E., Spodzieja, M., Kolodziejczyk, A.S., The Arctic mutation alters helix length and type in the 11-28 beta-amyloid peptide monomer-CD, NMR and MD studies in an SDS micelle (2008) J Struct Biol, , Advance online publication. Retrieved July 24, 2008. doi:10.1016/j.jsb. 2008.07.010
Beta-Amyloid Monomers Are Neuroprotective
The 42-aa-long beta-amyloid protein-A beta (1-42) -is thought to play a central role in the pathogenesis of Alzheimer's disease (AD) (Walsh and Selkoe, 2007). Data from AD brain (Shankar et al., 2008), transgenic APP (amyloid precursor protein) -overexpressing mice (Lesne et al., 2006), and neuronal cultures treated with synthetic A beta peptides (Lambert et al., 1998) indicate that self-association of A beta (1-42) monomers into soluble oligomers is required for neurotoxicity. The function of monomeric A beta (1-42) is unknown. The evidence that A beta (1-42) is present in the brain and CSF of normal individuals suggests that the peptide is physiologically active (Shoji, 2002). Here we show that synthetic A beta (1-42) monomers support the survival of developing neurons under conditions of trophic deprivation and protect mature neurons against excitotoxic death, a process that contributes to the overall neurodegeneration associated with AD. The neuroprotective action of A beta (1-42) monomers was mediated by the activation of the PI-3-K (phosphatidylinositol-3-kinase) pathway, and involved the stimulation of IGF-1 (insulin-like growth factor-1) receptors and/or other receptors of the insulin superfamily. Interestingly, monomers of A beta (1-42) carrying the Arctic mutation (E22G) associated with familiar AD (Nilsberth et al., 2001) were not neuroprotective. We suggest that pathological aggregation of A beta (1-42) may also cause neurodegeneration by depriving neurons of the protective activity of A beta (1-42) monomers. This "loss-of-function" hypothesis of neuronal death should be taken into consideration when designing therapies aimed at reducing A beta burden
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