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- Title
Reversal of neurological deficits by painless nerve growth factor in a mouse model of Rett syndrome.
- Authors
Tiberi, Alexia; Borgonovo, Giulia; Testa, Giovanna; Pacifico, Paola; Jacob, Ajesh; Caprio, Mariachiara Di; Totaro, Valentino; Calvello, Mariantonietta; Cattaneo, Antonino; Capsoni, Simona
- Abstract
Rett syndrome is a rare genetic neurodevelopmental disease, affecting 1 in over 10 000 females born worldwide, caused by de novo mutations in the X-chromosome-located methyl-CpG-binding protein 2 (MeCP2) gene. Despite the great effort put forth by the scientific community, a therapy for this devastating disease is still needed. Here, we tested the therapeutic effects of a painless mutein of the nerve growth factor (NGF), called human NGF painless (hNGFp), via a non-invasive intranasal delivery in female MeCP2 +/− mice. Of note, previous work had demonstrated a broad biodistribution of hNGFp in the mouse brain by the nasal delivery route. We report that (i) the long-term lifelong treatment of MeCP2 +/− mice with hNGFp, starting at 2 months of age, increased the chance of survival while also greatly improving behavioural parameters. Furthermore, when we assessed the phenotypic changes brought forth by (ii) a short-term 1-month-long hNGFp-treatment, starting at 3 months of age (right after the initial presentation of symptoms), we observed the rescue of a well known neuronal target population of NGF, cholinergic neurons in the medial septum. Moreover, we reveal a deficit in microglial morphology in MeCP2 +/− mice, completely reversed in treated animals. This effect on microglia is in line with reports showing microglia to be a TrkA-dependent non-neuronal target cell population of NGF in the brain. To understand the immunomodulatory activity of hNGFp, we analysed the cytokine profile after hNGFp treatment in MeCP2 +/− mice, to discover that the treatment recovered the altered expression of key neuroimmune-communication molecules, such as fractalkine. The overall conclusion is that hNGFp delivered intranasally can ameliorate symptoms in the MeCP2 +/− model of Rett syndrome, by exerting strong neuroprotection with a dual mechanism of action: directly on target neurons and indirectly via microglia.
- Subjects
NERVE growth factor; RETT syndrome; LABORATORY mice; INTRANASAL administration; ANIMAL disease models
- Publication
Brain: A Journal of Neurology, 2024, Vol 147, Issue 1, p122
- ISSN
0006-8950
- Publication type
Article
- DOI
10.1093/brain/awad282