In:
The Journal of Neuroscience, Society for Neuroscience, Vol. 29, No. 34 ( 2009-08-26), p. 10582-10587
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0270-6474
,
1529-2401
DOI:
10.1523/JNEUROSCI.1736-09.2009
Language:
English
Publisher:
Society for Neuroscience
Publication Date:
2009
detail.hit.zdb_id:
1475274-8
SSG:
12
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