title: The chemokine CXCL12 mediates the anti-amyloidogenic action of painless human nerve growth factor.
abstract: Nerve growth factor is a therapeutic candidate for Alzheimer's disease. Due to its pain-inducing activity, in current clinical trials nerve growth factor is delivered locally into the brain by neurosurgery, but data on the efficacy of local nerve growth factor delivery in decreasing amyloid-β deposition are not available. To reduce the nerve growth factor pain-inducing side effects, thus avoiding the need for local brain injection, we developed human painless nerve growth factor (hNGFp), inspired by the human genetic disease hereditary sensory and autonomic neuropathy type V. hNGFp has identical neurotrophic potency as wild-type human nerve growth factor, but a 10-fold lower pain sensitizing activity. In this study we first mimicked, in the 5xFAD mouse model, the intraparenchymal delivery of hNGFp used in clinical trials and found it to be ineffective in decreasing amyloid-β plaque load. On the contrary, the same dose of hNGFp delivered intranasally, which was widely biodistributed in the brain and did not induce pain, showed a potent anti-amyloidogenic action and rescued synaptic plasticity and memory deficits. We found that hNGFp acts on glial cells, modulating inflammatory proteins such as the soluble TNFα receptor II and the chemokine CXCL12. We further established that the rescuing effect by hNGFp is mediated by CXCL12, as pharmacological inhibition of CXCL12 receptor CXCR4 occludes most of hNGFp effects. These findings have significant therapeutic implications: (i) we established that a widespread exposure of the brain is required for nerve growth factor to fully exert its neuroprotective actions; and (ii) we have identified a new anti-neurodegenerative pathway as a broad target for new therapeutic opportunities for neurodegenerative diseases.
authors.affiliation: 1 Bio@SNS Laboratory of Biology, Scuola Normale Superiore, Pisa, Italy.|2 Institute of Neuroscience, National Council for Research, Pisa, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Capsoni
authors.affiliation: 1 Bio@SNS Laboratory of Biology, Scuola Normale Superiore, Pisa, Italy.|3 Neurotrophins and Neurodegenerative Diseases Laboratory, Rita Levi-Montalcini European Brain Research Institute, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Malerba
authors.affiliation: 1 Bio@SNS Laboratory of Biology, Scuola Normale Superiore, Pisa, Italy.
authors.forename: Nicola Maria
authors.initials: NM
authors.lastname: Carucci
authors.affiliation: 1 Bio@SNS Laboratory of Biology, Scuola Normale Superiore, Pisa, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Rizzi
authors.affiliation: 2 Institute of Neuroscience, National Council for Research, Pisa, Italy.|4 Department of Biotechnological and Applied Clinical Sciences, School of Medicine, University of L'Aquila, Coppito, L'Aquila, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Criscuolo
authors.affiliation: 2 Institute of Neuroscience, National Council for Research, Pisa, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Origlia
authors.affiliation: 1 Bio@SNS Laboratory of Biology, Scuola Normale Superiore, Pisa, Italy.
authors.forename: Mariantonietta
authors.initials: M
authors.lastname: Calvello
authors.affiliation: 1 Bio@SNS Laboratory of Biology, Scuola Normale Superiore, Pisa, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Viegi
authors.affiliation: 3 Neurotrophins and Neurodegenerative Diseases Laboratory, Rita Levi-Montalcini European Brain Research Institute, Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Meli
authors.affiliation: 1 Bio@SNS Laboratory of Biology, Scuola Normale Superiore, Pisa, Italy antonino.cattaneo@sns.it.|3 Neurotrophins and Neurodegenerative Diseases Laboratory, Rita Levi-Montalcini European Brain Research Institute, Rome, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Cattaneo
mesh_terms: D000281:Administration, Intranasal; D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D001522:Behavior, Animal; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D054377:Chemokine CXCL12 / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D008569:Memory Disorders / Q000188:drug therapy*; D051379:Mice; D008822:Mice, Transgenic; D020932:Nerve Growth Factor / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D009473:Neuronal Plasticity / Q000187:drug effects*; D010146:Pain / Q000139:chemically induced*; D058225:Plaque, Amyloid / Q000188:drug therapy*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; C502240:NGF protein, human; D019718:Receptors, CXCR4; D020932:Nerve Growth Factor
keywords: Alzheimer; CXCL12; intranasal; nerve growth factor; pain