β-Amyloid Monomers Are Neuroprotective

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 cult...

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Bibliographic Details
Published in:Journal of Neuroscience
Main Authors: Giuffrida, Maria Laura, Caraci, Filippo, Pignataro, Bruno, Cataldo, Sebastiano, De Bona, Paolo, Bruno, Valeria, Molinaro, Gemma, Pappalardo, Giuseppe, Messina, Angela, Palmigiano, Angelo, Garozzo, Domenico, Nicoletti, Ferdinando, Rizzarelli, Enrico, Copani, Agata
Format: Text
Language:English
Published: Society for Neuroscience 2009
Subjects:
Brief Communications
Arctic
Online Access:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6665714/
http://www.ncbi.nlm.nih.gov/pubmed/19710311
https://doi.org/10.1523/JNEUROSCI.1736-09.2009
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Summary: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.

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