TY - JOUR
T1 - β-amyloid monomers are neuroprotective
AU - Giuffrida, Maria Laura
AU - Caraci, Filippo
AU - Pignataro, Bruno
AU - Cataldo, Sebastiano
AU - De Bona, Paolo
AU - Bruno, Valeria
AU - Molinaro, Gemma
AU - Pappalardo, Giuseppe
AU - Messina, Angela
AU - Palmigiano, Angelo
AU - Garozzo, Domenico
AU - Nicoletti, Ferdinando
AU - Rizzarelli, Enrico
AU - Copani, Agata
PY - 2009/8/26
Y1 - 2009/8/26
N2 - The 42-aa-long β-amyloid protein - Aβ1-42 - isthought 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 Aβpeptides (Lambert et al., 1998) indicate that self-association of Aβ1-42 monomers into soluble oligomers is required for neurotoxicity. The function of monomeric Aβ1-42 is unknown. The evidence that Aβ1-42 is present in the brain and CSF of normal individuals suggests that the peptide is physiologically active (Shoji, 2002). Here we show that synthetic Aβ1-42 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 Aβ1-42 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 Aβ1-42 carrying the Arctic mutation (E22G) associated with familiar AD (Nilsberth et al., 2001) were not neuroprotective. We suggest that pathological aggregation of Aβ1-42 may also cause neurodegeneration by depriving neurons of the protective activity of Aβ1-42 monomers. This "loss-of-function" hypothesis of neuronal death should be taken into consideration when designing therapies aimed at reducing Aβ burden.
AB - The 42-aa-long β-amyloid protein - Aβ1-42 - isthought 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 Aβpeptides (Lambert et al., 1998) indicate that self-association of Aβ1-42 monomers into soluble oligomers is required for neurotoxicity. The function of monomeric Aβ1-42 is unknown. The evidence that Aβ1-42 is present in the brain and CSF of normal individuals suggests that the peptide is physiologically active (Shoji, 2002). Here we show that synthetic Aβ1-42 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 Aβ1-42 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 Aβ1-42 carrying the Arctic mutation (E22G) associated with familiar AD (Nilsberth et al., 2001) were not neuroprotective. We suggest that pathological aggregation of Aβ1-42 may also cause neurodegeneration by depriving neurons of the protective activity of Aβ1-42 monomers. This "loss-of-function" hypothesis of neuronal death should be taken into consideration when designing therapies aimed at reducing Aβ burden.
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U2 - 10.1523/JNEUROSCI.1736-09.2009
DO - 10.1523/JNEUROSCI.1736-09.2009
M3 - Article
C2 - 19710311
AN - SCOPUS:69449090793
SN - 0270-6474
VL - 29
SP - 10582
EP - 10587
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 34
ER -