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Cited by 423Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

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β-Amyloid Monomers Are Neuroprotective

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Giuffrida, Maria Laura, Caraci, Filippo, Pignataro, Bruno, Cataldo, Sebastiano, De Bona, Paolo, Bruno, Valeria, Molinaro, Gemma, Pappalardo, Giuseppe, Messina, Angela, Palmigiano, Angelo, Garozzo, Domenico, Nicoletti, Ferdinando, Rizzarelli, Enrico, Copani, Agata·2009·The Journal of Neuroscience
DOI 10.1523/jneurosci.1736-09.2009PMC PMC6665714
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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.

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Figure 1 A 𝛃 1-42 monomers: separation, characterization, and lack of neurotoxicity in culture. A , B , AFM images of low-mass ( < 10 kDa, A ) and high-mass ( > 50 kDa, B ) A 𝛃 1-42 species isolated from a single suspension by cutoff filters. The respective frequencies of species in the two samples are shown on the right side. The monomer fraction consisted primarily of small globules 1.3 nm in height (mean ± SD: 1.36 ± 0.42, n = 365). In contrast, the oligomer fraction consisted of larger globules 13 nm in height (mean ± SD: 13.5 ± 10.8, n = 207). In B , the asterisk indicates structures derived from the aggregation of several oligomer species which were excluded from the statistics. C , Representative Western blot image of Bcl-2 bands in control cultures (C) and cultures treated with < 10 kDa A 𝛃 1-42 for 6 h. 𝛃 -Actin bands are shown for control of loading. Quantitation of Bcl-2/ 𝛃 -actin ratios was as follows: control (C) = 0.7 ± 0.1; < 10kDaA 𝛃 1-42 = 1.2 ± 0.03*(means ± SEMofthreeindependentexperiments; *significantly different from control at p < 0.05 by Student's t test). Viability of pure cortical neurons, as measured by MTT assay, following 48 h treatment with different A 𝛃 1-42 fractions (all at 0.1 𝛍 M) or different concentrations of < 10 kDa A 𝛃 1-42 , is shown in D and E , respectively. Values are means ± SEM of eight determinations from two independent experiments. * p < 0.05 (one-way ANOVA + Fisher's LSD) compared with control (CTRL).
Figure 1 A 𝛃 1-42 monomers: separation, characterization, and lack of neurotoxicity in culture. A , B , AFM images of low-mass ( < 10 kDa, A ) and high-mass ( > 50 kDa, B ) A 𝛃 1-42 species isolated from a single suspension by cutoff filters. The respective frequencies of species in the two samples are shown on the right side. The monomer fraction consisted primarily of small globules 1.3 nm in height (mean ± SD: 1.36 ± 0.42, n = 365). In contrast, the oligomer fraction consisted of larger globules 13 nm in height (mean ± SD: 13.5 ± 10.8, n = 207). In B , the asterisk indicates structures derived from the aggregation of several oligomer species which were excluded from the statistics. C , Representative Western blot image of Bcl-2 bands in control cultures (C) and cultures treated with < 10 kDa A 𝛃 1-42 for 6 h. 𝛃 -Actin bands are shown for control of loading. Quantitation of Bcl-2/ 𝛃 -actin ratios was as follows: control (C) = 0.7 ± 0.1; < 10kDaA 𝛃 1-42 = 1.2 ± 0.03*(means ± SEMofthreeindependentexperiments; *significantly different from control at p < 0.05 by Student's t test). Viability of pure cortical neurons, as measured by MTT assay, following 48 h treatment with different A 𝛃 1-42 fractions (all at 0.1 𝛍 M) or different concentrations of < 10 kDa A 𝛃 1-42 , is shown in D and E , respectively. Values are means ± SEM of eight determinations from two independent experiments. * p < 0.05 (one-way ANOVA + Fisher's LSD) compared with control (CTRL).CC-BY-NC-SA · From the PDF
Figure 2 A 𝛃 1-42 monomerssupport neuronal survival via the activation of the PI-3-K pathway. A , Viability of pure cortical neurons,asmeasuredbyMTTassay,insulin-deprivedsinceplatingfor 1 week (no Ins), in the absence or presence of 0.1 𝛍 M A 𝛃 1-42 monomers [m A 𝛃 (1-42)]. Where required, the PI-3-K inhibitor, LY294002 (10 𝛍 M), was added two times (at plating and after 48 h). Values are means ± SEMofsixdeterminations from two independent experiments. * , ** ,# Different from control (CTRL) (*), no Ins (**), or no Ins + mA 𝛃 1-42 (#) at p < 0.05 by one-way ANOVA + Fisher's LSD test. B , Representative Western blot images of the PI-3-K-activated form of the serinethreonine kinase AKT [p(ser 473)-AKT], of the corresponding inactivated GSK-3 𝛃 [p(ser 9)-GSK-3 𝛃 ], and of 𝛃 -catenin levels in control cultures (C) and cultures treated with 0.1 𝛍 M monomeric A 𝛃 1-42 (mA 𝛃 ) for 10 min. Levels of phosphorylated ERK1/2 (pERK1/2) in the same cultures are also shown. Total AKT levels, 𝛃 -actin bands, or total ERK levels are shown for control of loading. Quantitation of p(ser 473)-AKT/AKT ratios was as follows: control (C) = 0.26 ± 0.04; mA 𝛃 1-42 = 0.65 ± 0.1* (means ± SEMofthree independent experiments; *significantly different from control at p < 0.05 by Student's t test). Quantitation of p(ser 9)-GSK-3 𝛃 /GSK-3 𝛃 ratios was as follows: control (C) = 0.88 ± 0.15; mA 𝛃 1-42 = 1.44 ± 0.08* (means ± SEM of three independent experiments; *significantly different from control at p < 0.05 by Student's t test). Quantitation of 𝛃 -catenin/ 𝛃 -actin ratios was as follows: control (C) = 0.47 ± 0.05; mA 𝛃 1-42 = 1.3 ± 0.09* (means ± SEM of three independent experiments; *significantly different from control at p < 0.05 by Student's t test). Quantitation of pERK 1/2/ERK 1/2 ratios was as follows: control (C) = 0.6 ± 0.08; mA 𝛃 1-42 = 0.55 ± 0.12 (means ± SEM of three independent experiments).
Figure 2 A 𝛃 1-42 monomerssupport neuronal survival via the activation of the PI-3-K pathway. A , Viability of pure cortical neurons,asmeasuredbyMTTassay,insulin-deprivedsinceplatingfor 1 week (no Ins), in the absence or presence of 0.1 𝛍 M A 𝛃 1-42 monomers [m A 𝛃 (1-42)]. Where required, the PI-3-K inhibitor, LY294002 (10 𝛍 M), was added two times (at plating and after 48 h). Values are means ± SEMofsixdeterminations from two independent experiments. * , ** ,# Different from control (CTRL) (*), no Ins (**), or no Ins + mA 𝛃 1-42 (#) at p < 0.05 by one-way ANOVA + Fisher's LSD test. B , Representative Western blot images of the PI-3-K-activated form of the serinethreonine kinase AKT [p(ser 473)-AKT], of the corresponding inactivated GSK-3 𝛃 [p(ser 9)-GSK-3 𝛃 ], and of 𝛃 -catenin levels in control cultures (C) and cultures treated with 0.1 𝛍 M monomeric A 𝛃 1-42 (mA 𝛃 ) for 10 min. Levels of phosphorylated ERK1/2 (pERK1/2) in the same cultures are also shown. Total AKT levels, 𝛃 -actin bands, or total ERK levels are shown for control of loading. Quantitation of p(ser 473)-AKT/AKT ratios was as follows: control (C) = 0.26 ± 0.04; mA 𝛃 1-42 = 0.65 ± 0.1* (means ± SEMofthree independent experiments; *significantly different from control at p < 0.05 by Student's t test). Quantitation of p(ser 9)-GSK-3 𝛃 /GSK-3 𝛃 ratios was as follows: control (C) = 0.88 ± 0.15; mA 𝛃 1-42 = 1.44 ± 0.08* (means ± SEM of three independent experiments; *significantly different from control at p < 0.05 by Student's t test). Quantitation of 𝛃 -catenin/ 𝛃 -actin ratios was as follows: control (C) = 0.47 ± 0.05; mA 𝛃 1-42 = 1.3 ± 0.09* (means ± SEM of three independent experiments; *significantly different from control at p < 0.05 by Student's t test). Quantitation of pERK 1/2/ERK 1/2 ratios was as follows: control (C) = 0.6 ± 0.08; mA 𝛃 1-42 = 0.55 ± 0.12 (means ± SEM of three independent experiments).CC-BY-NC-SA · From the PDF
Figure 3 A 𝛃 1-42 monomers protect neurons against NMDA toxicity. A , NMDA-induced toxicity in mixed cortical cultures is potentiated by oligomeric A 𝛃 1-42 [oA 𝛃 (1-42)] and ( B ) prevented by monomeric A 𝛃 1-42 [mA 𝛃 (1-42)]. Toxicity was induced by a 10 min pulse with 300 𝛍 M NMDA and assessed by trypan blue staining (set to 100%) 24 h later. In the prepulse condition, A 𝛃 1-42 monomerswereapplied24hbeforetheNMDApulseandcultureswereextensivelywashedbeforetheexperiment.Inthepostpulse condition, A 𝛃 1-42 monomers were applied soon after the excitotoxic pulse and kept for 24 h into the medium. Both in A and in B , values are means ± SEMof 9-18 determinations from three-six independent experiments. A , *Significantly different from the respective control (CTRL) at p < 0.05 (one-way ANOVA + Fisher's LSD test). B , *Significantly different from NMDA at p < 0.001 (one-way ANOVA + Fisher's LSD test). C , NMDA-induced toxicity in mixed cortical cultures is attenuated by the monomeric forms of A 𝛃 1-42 , A 𝛃 1-40 , and A 𝛃 42-1 , but not by A 𝛃 1-42 or A 𝛃 42-1 containing the Arctic mutation (m arcA 𝛃 ). Values are means ± SEM of 12-18 determinations from three-six independent experiments. *Significantly different from NMDAat p < 0.001(one-wayANOVA + Fisher's LSD test). D , The PI-3-K inhibitor LY 294002 (10 𝛍 M)preventstheneuroprotective activity of monomeric forms of A 𝛃 1-42 , A 𝛃 1-40 , and A 𝛃 42-1 . Values are means ± SEMof 8 determinations from two independent experiments. * ,# Significantly different from NMDA (*) or from the respective A 𝛃 conditions (#) at p < 0.05 (one-way ANOVA + Fisher's LSD test). [UO126] = 10 𝛍 M. E , The selective inhibitor of the insulin receptor superfamily, AG1024, and the preferential IGF-1 receptor inhibitor, picropodophyllin (PPP), prevent the neuroprotective activity of monomeric forms of A 𝛃 1-42 and A 𝛃 42-1 . Values are means ± SEMofeightdeterminations from two independent experiments. * ,# Significantly different from NMDA (*) or from the respective A 𝛃 conditions (#) at p < 0.05 (one-way ANOVA + Fisher's LSD test). F , Representative immunoblots of p(ser 473)-AKT, p(tyr 1179)-IRS1, and p(ser 302)-IRS1 in pure neuronal cultures treated with 0.1 𝛍 M monomeric A 𝛃 1-42 [mA 𝛃 (1-42)] for 5 min both in the absence and in the presence of 100 nM AG1024. Quantitation of p(ser 473)AKT/AKT ratios was as follows: control (C) = 0.5 ± 0.04; mA 𝛃 1-42 = 1.37 ± 0.1*; mA 𝛃 1-42 + AG1024 = 0.7 ± 0.08**; AG1024 = 0.55 ± 0.06 [means ± SEMof three independentexperiments;* , **significantlydifferentfromcontrol(*)ormA 𝛃 1-42 alone(**)at p < 0.05byone-wayANOVA + Fisher's LSD test]. Quantitation of p(tyr 1179)-IRS1/IRS1 ratios was as follows: control (C) = 0.42 ± 0.12; mA 𝛃 1-42 = 1.31 ± 0.03*; mA 𝛃 1-42 + AG1024 = 0.63 ± 0.02**; AG1024 = 0.65 ± 0.08 [means ± SEM of three independent experiments; * , **significantly different from control (*) or mA 𝛃 1-42 alone (**) at p < 0.05 by one-way ANOVA + Fisher's LSD test]. Quantitation of p(ser 302)-IRS1/IRS1 ratios was as follows: control (C) = 0.39 ± 0.09; mA 𝛃 1-42 = 0.85 ± 0.06*; mA 𝛃 1-42 + AG1024 = 0.28 ± 0.11**; AG1024 = 0.46 ± 0.08 [means ± SEMof three independent experiments; * , **significantly different from control (*) or mA 𝛃 1-42 (**) alone at p < 0.05 by one-way ANOVA + Fisher's LSD test].
Figure 3 A 𝛃 1-42 monomers protect neurons against NMDA toxicity. A , NMDA-induced toxicity in mixed cortical cultures is potentiated by oligomeric A 𝛃 1-42 [oA 𝛃 (1-42)] and ( B ) prevented by monomeric A 𝛃 1-42 [mA 𝛃 (1-42)]. Toxicity was induced by a 10 min pulse with 300 𝛍 M NMDA and assessed by trypan blue staining (set to 100%) 24 h later. In the prepulse condition, A 𝛃 1-42 monomerswereapplied24hbeforetheNMDApulseandcultureswereextensivelywashedbeforetheexperiment.Inthepostpulse condition, A 𝛃 1-42 monomers were applied soon after the excitotoxic pulse and kept for 24 h into the medium. Both in A and in B , values are means ± SEMof 9-18 determinations from three-six independent experiments. A , *Significantly different from the respective control (CTRL) at p < 0.05 (one-way ANOVA + Fisher's LSD test). B , *Significantly different from NMDA at p < 0.001 (one-way ANOVA + Fisher's LSD test). C , NMDA-induced toxicity in mixed cortical cultures is attenuated by the monomeric forms of A 𝛃 1-42 , A 𝛃 1-40 , and A 𝛃 42-1 , but not by A 𝛃 1-42 or A 𝛃 42-1 containing the Arctic mutation (m arcA 𝛃 ). Values are means ± SEM of 12-18 determinations from three-six independent experiments. *Significantly different from NMDAat p < 0.001(one-wayANOVA + Fisher's LSD test). D , The PI-3-K inhibitor LY 294002 (10 𝛍 M)preventstheneuroprotective activity of monomeric forms of A 𝛃 1-42 , A 𝛃 1-40 , and A 𝛃 42-1 . Values are means ± SEMof 8 determinations from two independent experiments. * ,# Significantly different from NMDA (*) or from the respective A 𝛃 conditions (#) at p < 0.05 (one-way ANOVA + Fisher's LSD test). [UO126] = 10 𝛍 M. E , The selective inhibitor of the insulin receptor superfamily, AG1024, and the preferential IGF-1 receptor inhibitor, picropodophyllin (PPP), prevent the neuroprotective activity of monomeric forms of A 𝛃 1-42 and A 𝛃 42-1 . Values are means ± SEMofeightdeterminations from two independent experiments. * ,# Significantly different from NMDA (*) or from the respective A 𝛃 conditions (#) at p < 0.05 (one-way ANOVA + Fisher's LSD test). F , Representative immunoblots of p(ser 473)-AKT, p(tyr 1179)-IRS1, and p(ser 302)-IRS1 in pure neuronal cultures treated with 0.1 𝛍 M monomeric A 𝛃 1-42 [mA 𝛃 (1-42)] for 5 min both in the absence and in the presence of 100 nM AG1024. Quantitation of p(ser 473)AKT/AKT ratios was as follows: control (C) = 0.5 ± 0.04; mA 𝛃 1-42 = 1.37 ± 0.1*; mA 𝛃 1-42 + AG1024 = 0.7 ± 0.08**; AG1024 = 0.55 ± 0.06 [means ± SEMof three independentexperiments;* , **significantlydifferentfromcontrol(*)ormA 𝛃 1-42 alone(**)at p < 0.05byone-wayANOVA + Fisher's LSD test]. Quantitation of p(tyr 1179)-IRS1/IRS1 ratios was as follows: control (C) = 0.42 ± 0.12; mA 𝛃 1-42 = 1.31 ± 0.03*; mA 𝛃 1-42 + AG1024 = 0.63 ± 0.02**; AG1024 = 0.65 ± 0.08 [means ± SEM of three independent experiments; * , **significantly different from control (*) or mA 𝛃 1-42 alone (**) at p < 0.05 by one-way ANOVA + Fisher's LSD test]. Quantitation of p(ser 302)-IRS1/IRS1 ratios was as follows: control (C) = 0.39 ± 0.09; mA 𝛃 1-42 = 0.85 ± 0.06*; mA 𝛃 1-42 + AG1024 = 0.28 ± 0.11**; AG1024 = 0.46 ± 0.08 [means ± SEMof three independent experiments; * , **significantly different from control (*) or mA 𝛃 1-42 (**) alone at p < 0.05 by one-way ANOVA + Fisher's LSD test].CC-BY-NC-SA · From the PDF

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Metadata

Authors
Giuffrida, M. L., 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.
Affiliations
  • University of Catania (IT)
  • University of Palermo (IT)
  • Istituto Neurologico Mediterraneo (IT)
  • Institute of Biostructure and Bioimaging (IT)
  • National Research Council (IT)
ORCID
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2009-08-26
Volume
29
Issue
34
Pages
10582-10587
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
DOI
10.1523/jneurosci.1736-09.2009
PMC
PMC6665714
OpenAlex
W1991988242
Cited by
421
References
33
Citations by year
2026: 10 · 2025: 19 · 2024: 30 · 2023: 27 · 2022: 21 · 2021: 34 · 2020: 23 · 2019: 21 · 2018: 27 · 2017: 30 · 2016: 22 · 2015: 23 · 2014: 31 · 2013: 23 · 2012: 18
FWCI
17.73
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Nova Science Publishers (Nova Science Publishers, Inc.) (submittedVersion, other-oa)
  • IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
Funders
Università di Catania
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
amyloid-beta 42, neuroprotection, Alzheimer's disease, excitotoxicity, IGF-1 receptor, Arctic mutation, amyloid fibril formation, neurodegeneration
MeSH terms
Analysis of Variance, Animals, Butadienes, Cells, Cultured, Cerebral Cortex, Dose-Response Relationship, Drug, Embryo, Mammalian, Enzyme Inhibitors, Neurons, Nitriles, Peptide Fragments, Podophyllotoxin, N-Methylaspartate, Amyloid beta-Peptides, Cell Death, Excitatory Amino Acid Agonists, Neuroprotective Agents, Tyrphostins, Rats

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