Soluble oligomeric forms of beta-amyloid (Aβ) peptide stimulate Aβ production via astrogliosis in the rat brain

Pérez, J L Martínez; Carrero, Isabel; Gonzalo, Pilar; Arévalo-Serrano, Juan; Sanz‐Anquela, José Miguel; Ortega, Francisco J.; Rodrı́guez, Manuel J.; Gonzalo-Ruiz, A.

doi:10.1016/j.expneurol.2009.10.013

Cited by 35 publications

(26 citation statements)

References 81 publications

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“…Furthermore, our results showed that Aβo treatment increased Aβ production markers in SH-SY5Y-APP cells, which is consistent with available literature studies (Perez et al, 2010). However, our results also suggest that Aβo not only induce the expression of APP, but also modulate the processing of APP where Aβo selectively increased the levels of sAPPβ (a product of secretase-β), compared to sAPPα (a product of secretase-α), which suggest that Aβo induce secretase-β activity and thus further contribute to the pathological load of Aβ.…”

Section: Discussionsupporting

confidence: 93%

Oleocanthal ameliorates amyloid-β oligomers’ toxicity on astrocytes and neuronal cells: In vitro studies

et al. 2017

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Extra-virgin olive oil (EVOO) has several health promoting effects. Evidence have shown that EVOO attenuates the pathology of amyloid-β (Aβ) and improves cognitive function in experimental animal models, suggesting it’s potential to protect and reduce the risk of developing Alzheimer’s disease (AD). Available studies have linked this beneficial effect to oleocanthal, one of the active components in EVOO. The effect of oleocanthal against AD pathology has been linked to its ability to attenuate Aβ and tau aggregation in vitro, and enhance Aβ clearance from the brains of wild type and AD transgenic mice in vivo. However, the ability of oleocanthal to alter the toxic effect of Aβ on brain parenchymal cells is unknown. In the current study, we investigated oleocanthal effect on modulating Aβ oligomers (Aβo) pathological events in neurons and astrocytes. Our findings demonstrated oleocanthal prevented Aβo-induced synaptic proteins, SNAP-25 and PSD-95, down-regulation in neurons, and attenuated Aβo-induced inflammation, glutamine transporter (GLT1) and glucose transporter (GLUT1) down-regulation in astrocytes. Aβo-induced inflammation was characterized by interleukin-6 (IL-6) increase and glial fibrillary acidic protein (GFAP) upregulation that were reduced by oleocanthal. In conclusion, this study provides further evidence to support the protective effect of EVOO-derived phenolic secoiridoid oleocanthal against AD pathology.

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Section: Discussionsupporting

confidence: 93%

Oleocanthal ameliorates amyloid-β oligomers’ toxicity on astrocytes and neuronal cells: In vitro studies

et al. 2017

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“…Astrocytes occur in close association with amyloid plaques and they can take up and degrade extracellular amyloid (Wyss-Coray et al, 2003). Furthermore, colocalization of Aβ immunoreactive extracellular matrix and GFAP immunoreactivity was recently reported by Perez and colleagues (Perez et al, 2010) after injection of Aβ 1-40 in rat brain.…”

Section: Inos Nnos and Astrogliosismentioning

confidence: 72%

Genistein inhibits aggregation of exogenous amyloid-beta1–40 and alleviates astrogliosis in the hippocampus of rats

et al. 2012

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We addressed the question of whether injection of Aβ in the rat brain is associated with pathology in the hippocampus, and if genistein has any protective effect against the neuronal damage caused by Aβ 1-40 . Genistein is a plant-derived compound with a structure similar to that of the female sex hormone oestrogen and it was recently shown that pretreatment with a single dose of genistein ameliorated learning and memory deficits in an amyloid beta (Aβ) 1-40 rat model of Alzheimer's disease. Here, we report that injection of the amyloid peptide into the hippocampus of rats led to formation of Aβ 1-40 positive aggregates close to the lateral blade of the dentate gyrus (DGlb). We also observed the following in the hippocampus: extensive cell death in the DGlb (P < 0.0001), CA1 (P = 0.03), and CA3 (P = 0.002); an increased number of iNOS-expressing cells (P = 0.01) and gliosis. Genistein given to rats by gavage one hour before Key words: amyloid-beta, Alzheimer's disease, genistein, neuronal degeneration 1 1 Abbreviations: AD, Alzheimer's disease; iNOS, inducible nitric oxide synthase; nNOS, neuronal nitric oxide synthase; CA1, cornu ammonis 1; CA2, cornu ammonis 2; CA3, cornu ammonis 3; Aβ, amyloid beta; DGlb, lateral blade of dentate gyrus; DGmb, medial blade of dentate gyrus; GFAP, glial fibrillary acidic protein; CC, corpus callosum; MAP, mitogenactivated protein; NFĸB, nuclear factor kappa B; MnSOD, manganese superoxide dismutase; APP, amyloid precursor protein; CrEL, Cremophor EL

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“…Although most research has focused on the effect of Tau protein tangles and A␤ plaques on neuronal function and survival, it is now well established that astrocytes also play a role in AD pathology (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). In the CNS, astrocytes are indispensable for the support of neurons.…”

Section: Alzheimer Disease (Ad)mentioning

confidence: 99%

Astrocytes Secrete Exosomes Enriched with Proapoptotic Ceramide and Prostate Apoptosis Response 4 (PAR-4)

Wang¹,

Dinkins²,

He³

et al. 2012

Journal of Biological Chemistry

332

305

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Background:In AD, amyloid protein is associated with neurodegeneration, which may involve amyloid effects on astrocytes. Results: In astrocytes, amyloid peptide triggers secretion of proapoptotic exosomes ("apoxosomes") that are associated with ceramide and PAR-4. Conclusion: Activation of nSMase2 and expression of PAR-4 is critical for the secretion of apoxosomes and glial apoptosis. Significance: Apoxosomes may contribute to glial apoptosis, and therefore, neurodegeneration in AD.Amyloid protein is well known to induce neuronal cell death, whereas only little is known about its effect on astrocytes. We found that amyloid peptides activated caspase 3 and induced apoptosis in primary cultured astrocytes, which was prevented by caspase 3 inhibition. Apoptosis was also prevented by shRNA-mediated down-regulation of PAR-4, a protein sensitizing cells to the sphingolipid ceramide. Consistent with a potentially proapoptotic effect of PAR-4 and ceramide, astrocytes surrounding amyloid plaques in brain sections of the 5xFAD mouse (and Alzheimer disease patient brain) showed caspase 3 activation and were apoptotic when co-expressing PAR-4 and ceramide. Apoptosis was not observed in astrocytes with deficient neutral sphingomyelinase 2 (nSMase2), indicating that ceramide generated by nSMase2 is critical for amyloid-induced apoptosis. Antibodies against PAR-4 and ceramide prevented amyloid-induced apoptosis in vitro and in vivo, suggesting that apoptosis was mediated by exogenous PAR-4 and ceramide, potentially associated with secreted lipid vesicles. This was confirmed by the analysis of lipid vesicles from conditioned medium showing that amyloid peptide induced the secretion of PAR-4 and C18 ceramide-enriched exosomes. Exosomes were not secreted by nSMase2-deficient astrocytes, indicating that ceramide generated by nSMase2 is critical for exosome secretion. Consistent with the ceramide composition in amyloid-induced exosomes, exogenously added C18 ceramide restored PAR-4-containing exosome secretion in nSMase2-deficient astrocytes. Moreover, isolated PAR-4/ceramide-enriched exosomes were taken up by astrocytes and induced apoptosis in the absence of amyloid peptide. Taken together, we report a novel mechanism of apoptosis induction by PAR-4/ceramide-enriched exosomes, which may critically contribute to Alzheimer disease.

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Soluble oligomeric forms of beta-amyloid (Aβ) peptide stimulate Aβ production via astrogliosis in the rat brain

Cited by 35 publications

References 81 publications

Oleocanthal ameliorates amyloid-β oligomers’ toxicity on astrocytes and neuronal cells: In vitro studies

Oleocanthal ameliorates amyloid-β oligomers’ toxicity on astrocytes and neuronal cells: In vitro studies

Genistein inhibits aggregation of exogenous amyloid-beta1–40 and alleviates astrogliosis in the hippocampus of rats

Astrocytes Secrete Exosomes Enriched with Proapoptotic Ceramide and Prostate Apoptosis Response 4 (PAR-4)

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