4 results on '"Malerba, Francesca"'
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2. ProNGF Is a Cell‐Type‐Specific Mitogen for Adult Hippocampal and for Induced Neural Stem Cells
- Author
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Corvaglia, Valerio, Cilli, Domenica, Scopa, Chiara, Brandi, Rossella, Arisi, Ivan, Malerba, Francesca, La Regina, Federico, Scardigli, Raffaella, and Cattaneo, Antonino
- Abstract
The role of proNGF, the precursor of nerve growth factor (NGF), in the biology of adult neural stem cells (aNSCs) is still unclear. Here, we analyzed adult hippocampal neurogenesis in AD11 transgenic mice, in which the constitutive expression of anti‐NGF antibody leads to an imbalance of proNGF over mature NGF. We found increased proliferation of progenitors but a reduced neurogenesis in the AD11 dentate gyrus (DG)‐hippocampus (HP). Also in vitro, AD11 hippocampal neural stem cells (NSCs) proliferated more, but were unable to differentiate into morphologically mature neurons. By treating wild‐type hippocampal progenitors with the uncleavable form of proNGF (proNGF‐KR), we demonstrated that proNGF acts as mitogen on aNSCs at low concentration. The mitogenic effect of proNGF was specifically addressed to the radial glia‐like (RGL) stem cells through the induction of cyclin D1 expression. These cells express high levels of p75NTR, as demonstrated by immunofluorescence analyses performed ex vivo on RGL cells isolated from freshly dissociated HP‐DG or selected in vitro from NSCs by leukemia inhibitory factor. Clonogenic assay performed in the absence of mitogens showed that RGLs respond to proNGF‐KR by reactivating their proliferation and thus leading to neurospheres formation. The mitogenic effect of proNGF was further exploited in the expansion of mouse‐induced neural stem cells (iNSCs). Chronic exposure of iNSCs to proNGF‐KR increased their proliferation. Altogether, we demonstrated that proNGF acts as mitogen on hippocampal and iNSCs. Stem Cells2019;37:1223–1237 Possible mechanism of action of the precursor of nerve growth factor in the hippocampal neurogenic niche. The scheme represents the maturation from quiescent radial glia‐like stem cells to neuroblasts. p75NTRprotein level decreases during the maturation path. Precursor of nerve growth factor produced within the niche is partially cleaved to release mature nerve growth factor, whereas some precursor of nerve growth factor remains unprocessed. This portion of precursor of nerve growth factor switches the quiescent radial glia‐like stem cells to the active state by cyclin D1 induction. Mature nerve growth factor acts at the end of the maturation path by promoting neuroblast survival. Finally, in our hypothesis, precursor of nerve growth factor drives programmed cell death in neuroblasts, so the incessant regulation of precursor of nerve growth factor cleavage is determinant for a balanced neurogenesis. more...
- Published
- 2019
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3. Intranasal delivery of therapeutic proteins for neurological diseases
- Author
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Malerba, Francesca, Paoletti, Francesca, Capsoni, Simona, and Cattaneo, Antonino
- Abstract
Introduction: Among the range of therapeutic protein candidates for new generation treatments of neurological diseases, neurotrophic factors and recombinant antibodies hold the greatest potential. However, major difficulties in their safe and effective delivery to the brain severely limit these applications. The BBB restricts the exchange of proteins between the plasma and the CNS. Moreover, therapeutic proteins often need to be selectively targeted to the brain, while minimizing their biodistribution to systemic compartments, to avoid peripheral side effects. The intranasal delivery of proteins has recently emerged as a non-invasive, safe and effective method to target proteins to the CNS, bypassing the BBB and minimizing systemic exposure.Areas covered: We critically summarize the main experimental and mechanistic facts about the simple and non-invasive nasal delivery approach, which provides a promising strategy and a potential solution for the severe unmet medical need of safely and effectively delivering protein therapeutics to the brain.Expert opinion: The intranasal route for the effective delivery of recombinant therapeutic proteins represents an emerging and promising non-invasive strategy. Future studies will achieve a detailed understanding of pharmacokinetic and mechanisms of delivery to optimize formulations and fully exploit the nose-to-brain interface in order to deliver proteins for the treatment of neurological diseases. This expanding research area will most likely produce exciting results in the near future towards new therapeutical approaches for the CNS. more...
- Published
- 2011
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4. A Quantitative Bioassay to Determine the Inhibitory Potency of NGF–TrkA Antagonists
- Author
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Malerba, Francesca, Bruni Ercole, Bruno, Florio, Rita, and Cattaneo, Antonino
- Abstract
In this article, we demonstrate and validate a new bioassay named the NTAB [NGF–TrkA (nerve growth factor–tropomyosin receptor kinase A) antagonist bioassay] for the determination of the inhibitory potency of NGF–TrkA antagonists, based on the inhibition of NGF-dependent proliferation of the human TF1 erythroleukemic cell line.It is well known that NGF holds great therapeutic potential due to its neurotrophic and neuroprotective properties. NGF is also involved in some pathways, however, principally driven by TrkA that, if not correctly regulated, can lead to unwanted pathological outcomes linked to pain, angiogenesis, and cancer.Indeed, there is an increasing interest, from a therapeutic perspective, in designing new effective molecules (antibodies, antibody fragments, or small molecules) able to inhibit the undesired NGF–TrkA pathway. For these reasons, there is an interest to develop functional cell-based assays for determination of the inhibition potency of compounds inhibiting the NGF–TrkA axis. The NTAB presents significant advantages over other published NGF–TrkA functional bioassays, for these reasons: (1) It is quantitative, (2) it measures a pure TrkA response, (3) it is simpler, (4) it is based on a natural biological response, and (5) it is easily scalable from a lab scale to an automated industrial assay.The NTAB assay was validated with a panel of well-characterized NGF–TrkA inhibitors, yielding characteristic dose–response curves, from which the relative strength of the inhibitors was quantitatively determined and used for comparisons. This new bioassay will be very useful to assist in the validation and prioritization of the best inhibitors among a large number of candidates. more...
- Published
- 2021
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