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The Journal of Neuroscience, August 26, 2009, 29(34):10582-10587; doi:10.1523/JNEUROSCI.1736-09.2009

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Brief Communications
β-Amyloid Monomers Are Neuroprotective

Maria Laura Giuffrida,¹ Filippo Caraci,¹ Bruno Pignataro,² Sebastiano Cataldo,² Paolo De Bona,³ Valeria Bruno,^4,5 Gemma Molinaro,⁵ Giuseppe Pappalardo,⁶ Angela Messina,⁷ Angelo Palmigiano,⁷ Domenico Garozzo,⁷ Ferdinando Nicoletti,^4,5 Enrico Rizzarelli,^3,8 and Agata Copani^1,6

¹Department of Pharmaceutical Sciences, University of Catania, Catania 95125, Italy, ²Department of Physical-Chemistry, University of Palermo, Palermo 90100, Italy, ³Department of Chemical Sciences, University of Catania, Catania 95125, Italy, ⁴Department of Human Physiology and Pharmacology, University of Rome "La Sapienza," Rome 00185, Italy, ⁵Istituto Neurologico Mediterraneo, Neuromed, Pozzilli 86077, Italy, ⁶Institute of Biostructure and Bioimaging, National Research Council, Catania 95125, Italy, ⁷Istituto di Chimica e Tecnologia dei Polimeri–Consiglio Nazionale delle Ricerche, Catania 95126, Italy, and ⁸Istituto Nazionale Biostrutture e Biosistemi, Rome 00136, Italy

Correspondence should be addressed to Dr. Agata Copani, Department of Pharmaceutical Sciences, University of Catania, Viale Andrea Doria 6, 95125 Catania, Italy. Email: acopani{at}katamail.com

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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Received April 10, 2009; revised May 9, 2009; accepted July 13, 2009.

Correspondence should be addressed to Dr. Agata Copani, Department of Pharmaceutical Sciences, University of Catania, Viale Andrea Doria 6, 95125 Catania, Italy. Email: acopani{at}katamail.com

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