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.

beta-Amyloid Monomers Are Neuroprotective / 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. - In: THE JOURNAL OF NEUROSCIENCE. - ISSN 0270-6474. - STAMPA. - 29:34(2009), pp. 10582-10587. [10.1523/jneurosci.1736-09.2009]

beta-Amyloid Monomers Are Neuroprotective

BRUNO, Valeria Maria Gloria;NICOLETTI, Ferdinando;
2009

Abstract

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.
2009
01 Pubblicazione su rivista::01a Articolo in rivista
beta-Amyloid Monomers Are Neuroprotective / 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. - In: THE JOURNAL OF NEUROSCIENCE. - ISSN 0270-6474. - STAMPA. - 29:34(2009), pp. 10582-10587. [10.1523/jneurosci.1736-09.2009]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/228078
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