ABSTRACT
Title
Microglia-derived microvesicles convert Aβ 1-42 amyloid peptide from inert to neurotoxic
Authors
C. Verderio1, E. Turola1, A. Bergami2, G. Comi2, G. Magnani2, G. Martino2, R. Furlan2 and M. Matteoli1
1 Dept. of Pharmacology and CNR Institute of Neuroscience, Milano, Italy; 2 HSR, Milano, Italy
1 Dept. of Pharmacology and CNR Institute of Neuroscience, Milano, Italy; 2 HSR, Milano, Italy
Abstract
Cells communicate not only via chemical signals, but also via microvesicles (MVs) which are released into the intercellular space and which can carry signals, either on their membrane or in their lumen. Our previous results indicated that MVs, shed from reactive microglia, store and release the inflammatory cytokine IL1-beta (Bianco et al., 2005; Bianco et al., 2009). This cytokine is increased in brains of patients affected by Alzheimer’s Disease (AD), where amyloid deposition induces the activation of microglia and the production of inflammatory molecules. IL1-beta-containing MVs produced by reactive microglia might in principle contribute to neurodegeneration via at least two mechanisms: first, they may provide the lipid component which was reported to disassemble amyloid fibrils into oligomers or other prefibrillar precursors, which are the main neurotoxic amyloid species; second, amyloidogenic polypeptides could interact and penetrate into the lipid bilayers of MVs, thus favouring MV disruption an inducing the release of neurotoxic compounds.
We have recently detected significantly higher levels (more than ten folds) of microglia/macrophages-derived MVs in the CSF of AD but not MCI (Mild Cognitive Impairment) or FTD (Frontotemporal Dementia) patients as compared to sex- and aged-matched healthy controls (number of CSF analyzed so far: 24 AD, 7 MCI, 4 FTD, 9 age-matched controls). This in line with the observation that the amount of MVs in the CSF reflects the activation state of microglia/macrophages in vivo (Verderio et al., submitted). To get insights into the possible role of MVs in AD, we investigated the effects of MVs pre-exposed to 5 mM Ab1-42 on cultured neurons. We found that MVs isolated from microglia pre-incubated overnight with Ab1-42 but not Ab1-42 or MVs alone strongly affect the number of viable neurons, as indicated by annexin-V or propidium iodide staining . Dendrites of neurons exposed to Ab1-42-treated-MVs had a fragmented appearance and displayed abnormal cytoplasmic calcium concentration. Interestingly, neuronal damage induced by Ab1-42-treated MVs was strongly inhibited by glutamatergic antagonists, suggesting an excitotoxicity insult. Similar detrimental effects were induced in cultured neurons by MVs isolated from AD CSF, pre-incubated with Ab1-42. These data indicate that microglia/macrophages-derived MVs are sufficient to convert Ab1-42 amyloid peptide from inert to neurotoxic. The clarification of the pathogenic mechanisms by which MVs enhance Ab1-42 neurotoxicity may open new therapeutical strategies for the treatment of the disease.
Bianco F, Pravettoni E, Colombo A, Schenk U, Möller T, Matteoli M, Verderio C. (2005)Astrocyte-derived ATP induces vesicle shedding and IL-1beta release from microglia. J Immunol. 1;174(11):7268-77.
Bianco F, Perrotta C, Novellino L, Francolini M, Riganti L, Menna E, Saglietti L, Schuchman EH, Furlan R, Clementi E, Matteoli M, Verderio C. (2009) Acid sphingomyelinase activity triggers microparticle release from glial cells EMBO J. 22;28(8):1043-54.
Verderio C., Muzio L., Turola E., Bergami A., Novellino L., Ruffini F., Riganti L., Corradini I., Francolini M., Garzetti L., Maiorino C., Servida F., Vercelli A., Della Libera D., Martinelli V., Comi G., Martino G., Matteoli M. and Furlan R. Microvesicles in the cerebrospinal fluid reflect microglia/macrophage activation in rodent and human neuro-inflammation. Submitted.
We have recently detected significantly higher levels (more than ten folds) of microglia/macrophages-derived MVs in the CSF of AD but not MCI (Mild Cognitive Impairment) or FTD (Frontotemporal Dementia) patients as compared to sex- and aged-matched healthy controls (number of CSF analyzed so far: 24 AD, 7 MCI, 4 FTD, 9 age-matched controls). This in line with the observation that the amount of MVs in the CSF reflects the activation state of microglia/macrophages in vivo (Verderio et al., submitted). To get insights into the possible role of MVs in AD, we investigated the effects of MVs pre-exposed to 5 mM Ab1-42 on cultured neurons. We found that MVs isolated from microglia pre-incubated overnight with Ab1-42 but not Ab1-42 or MVs alone strongly affect the number of viable neurons, as indicated by annexin-V or propidium iodide staining . Dendrites of neurons exposed to Ab1-42-treated-MVs had a fragmented appearance and displayed abnormal cytoplasmic calcium concentration. Interestingly, neuronal damage induced by Ab1-42-treated MVs was strongly inhibited by glutamatergic antagonists, suggesting an excitotoxicity insult. Similar detrimental effects were induced in cultured neurons by MVs isolated from AD CSF, pre-incubated with Ab1-42. These data indicate that microglia/macrophages-derived MVs are sufficient to convert Ab1-42 amyloid peptide from inert to neurotoxic. The clarification of the pathogenic mechanisms by which MVs enhance Ab1-42 neurotoxicity may open new therapeutical strategies for the treatment of the disease.
Bianco F, Pravettoni E, Colombo A, Schenk U, Möller T, Matteoli M, Verderio C. (2005)Astrocyte-derived ATP induces vesicle shedding and IL-1beta release from microglia. J Immunol. 1;174(11):7268-77.
Bianco F, Perrotta C, Novellino L, Francolini M, Riganti L, Menna E, Saglietti L, Schuchman EH, Furlan R, Clementi E, Matteoli M, Verderio C. (2009) Acid sphingomyelinase activity triggers microparticle release from glial cells EMBO J. 22;28(8):1043-54.
Verderio C., Muzio L., Turola E., Bergami A., Novellino L., Ruffini F., Riganti L., Corradini I., Francolini M., Garzetti L., Maiorino C., Servida F., Vercelli A., Della Libera D., Martinelli V., Comi G., Martino G., Matteoli M. and Furlan R. Microvesicles in the cerebrospinal fluid reflect microglia/macrophage activation in rodent and human neuro-inflammation. Submitted.