title: Beta-amyloid monomers are neuroprotective.
abstract: The 42-aa-long beta-amyloid protein--Abeta(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 Abeta peptides (Lambert et al., 1998) indicate that self-association of Abeta(1-42) monomers into soluble oligomers is required for neurotoxicity. The function of monomeric Abeta(1-42) is unknown. The evidence that Abeta(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 Abeta(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 Abeta(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 Abeta(1-42) carrying the Arctic mutation (E22G) associated with familiar AD (Nilsberth et al., 2001) were not neuroprotective. We suggest that pathological aggregation of Abeta(1-42) may also cause neurodegeneration by depriving neurons of the protective activity of Abeta(1-42) monomers. This "loss-of-function" hypothesis of neuronal death should be taken into consideration when designing therapies aimed at reducing Abeta burden.
authors.affiliation: Department of Pharmaceutical Sciences, University of Catania, Catania 95125, Italy.
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Giuffrida
authors.forename: Filippo
authors.initials: F
authors.lastname: Caraci
authors.forename: Bruno
authors.initials: B
authors.lastname: Pignataro
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Cataldo
authors.forename: Paolo
authors.initials: P
authors.lastname: De Bona
authors.forename: Valeria
authors.initials: V
authors.lastname: Bruno
authors.forename: Gemma
authors.initials: G
authors.lastname: Molinaro
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pappalardo
authors.forename: Angela
authors.initials: A
authors.lastname: Messina
authors.forename: Angelo
authors.initials: A
authors.lastname: Palmigiano
authors.forename: Domenico
authors.initials: D
authors.lastname: Garozzo
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
authors.forename: Enrico
authors.initials: E
authors.lastname: Rizzarelli
authors.forename: Agata
authors.initials: A
authors.lastname: Copani
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D016202:N-Methylaspartate / Q000633:toxicity; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009570:Nitriles / Q000494:pharmacology; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D011034:Podophyllotoxin / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D002070:Butadienes; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D018696:Neuroprotective Agents; D009570:Nitriles; D010446:Peptide Fragments; D020032:Tyrphostins; C113580:U 0126; C075222:amyloid beta-protein (1-42); C447031:tyrphostin AG 1024; C415032:picropodophyllin; D016202:N-Methylaspartate; D011034:Podophyllotoxin