| Title | Beta-amyloid monomers are neuroprotective. | | Author(s) | Giuffrida ML, Caraci F, Pignataro B, Cataldo S, De Bona P, Bruno V, Molinaro G, Pappalardo G, Messina A, Palmigiano A, Garozzo D, Nicoletti F, Rizzarelli E, Copani A | | Institution | Department of Pharmaceutical Sciences, University of Catania, Catania 95125, Italy. | | Source | J Neurosci 2009 Aug 26; 29(34):10582-7. | | MeSH | Amyloid beta-Protein
Analysis of Variance
Animals
Butadienes
Cell Death
Cells, Cultured
Cerebral Cortex
Dose-Response Relationship, Drug
Embryo, Mammalian
Enzyme Inhibitors
Excitatory Amino Acid Agonists
N-Methylaspartate
Neurons
Neuroprotective Agents
Nitriles
Peptide Fragments
Podophyllotoxin
Rats
Tyrphostins
| | 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. | | Language | eng | | Pub Type(s) | Journal Article
Research Support, Non-U.S. Gov't
| | PubMed ID | 19710311 |
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