beta-Amyloid Monomers Are Neuroprotective

• Published in: Journal of Neuroscience
• Main Authors: M. L. Giuffrida, F. Caraci, B. Pignataro, S. Cataldo, P. De Bona, Gemma Molinaro, G. Pappalardo, A. Messina, A. Palmigiano, D. Garozzo, E. Rizzarelli, A. Copani, BRUNO, Valeria Maria Gloria, NICOLETTI, Ferdinando
• Other Authors: M. L., Giuffrida, F., Caraci, B., Pignataro, S., Cataldo, P., De Bona, Bruno, Valeria Maria Gloria, Gemma, Molinaro, G., Pappalardo, A., Messina, A., Palmigiano, D., Garozzo, Nicoletti, Ferdinando, E., Rizzarelli, A., Copani
• Format: Article in Journal/Newspaper
• Language: English
• Published: SOC NEUROSCIENCE 2009
• Subjects: Arctic
• Online Access: http://hdl.handle.net/11573/228078; https://doi.org/10.1523/jneurosci.1736-09.2009; http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=000269317900013&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=0c7ff228ccbaaa74236f48834a34396a; http://www.scopus.com/inward/record.url?eid=2-s2.0-69449090793&partnerID=65&md5=c431cbb3916b646da7e17887392c7abc

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.