Beta-amyloid monomers are neuroprotective.
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.
Giuffrida
Maria Laura
ML
Department of Pharmaceutical Sciences, University of Catania, Catania 95125, Italy.
Caraci
Filippo
F
Pignataro
Bruno
B
Cataldo
Sebastiano
S
De Bona
Paolo
P
Bruno
Valeria
V
Molinaro
Gemma
G
Pappalardo
Giuseppe
G
Messina
Angela
A
Palmigiano
Angelo
A
Garozzo
Domenico
D
Nicoletti
Ferdinando
F
Rizzarelli
Enrico
E
Copani
Agata
A
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
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