Beta-amyloid monomers are neuroprotective

The 42-aa-long beta-amyloid protein-A beta(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 (Lesne et al., 2006), and neuronal cultures treated with synthetic A beta peptides (Lambert et al., 1998) indicate that self-association of A beta(1-42) monomers into soluble oligomers is required for neurotoxicity. The function of monomeric A beta(1-42) is unknown. The evidence that A beta(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 A beta(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 A beta(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 A beta(1-42) carrying the Arctic mutation (E22G) associated with familiar AD (Nilsberth et al., 2001) were not neuroprotective. We suggest that pathological aggregation of A beta(1-42) may also cause neurodegeneration by depriving neurons of the protective activity of A beta(1-42) monomers. This "loss-of-function" hypothesis of neuronal death should be taken into consideration when designing therapies aimed at reducing A beta burden.