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β-Amyloid Monomers Are Neuroprotective

2009; Society for Neuroscience; Volume: 29; Issue: 34 Linguagem: Inglês

10.1523/jneurosci.1736-09.2009

1529-2401

Maria Laura Giuffrida, Filippo Caraci, Bruno Pignataro, Sebastiano Cataldo, Paolo De Bona, Valeria Bruno, Gemma Molinaro, Giuseppe Pappalardo, Angela Messina, Angelo Palmigiano, Domenico Garozzo, Ferdinando Nicoletti, Enrico Rizzarelli, Agata Copani,

S100 Proteins and Annexins

The 42-aa-long β-amyloid protein—Aβ 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 (Lesné et al., 2006), and neuronal cultures treated with synthetic Aβ peptides (Lambert et al., 1998) indicate that self-association of Aβ 1-42 monomers into soluble oligomers is required for neurotoxicity. The function of monomeric Aβ 1-42 is unknown. The evidence that Aβ 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 Aβ 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 Aβ 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 Aβ 1-42 carrying the Arctic mutation (E22G) associated with familiar AD (Nilsberth et al., 2001) were not neuroprotective. We suggest that pathological aggregation of Aβ 1-42 may also cause neurodegeneration by depriving neurons of the protective activity of Aβ 1-42 monomers. This “loss-of-function” hypothesis of neuronal death should be taken into consideration when designing therapies aimed at reducing Aβ burden.