title: ProNGF\NGF imbalance triggers learning and memory deficits, neurodegeneration and spontaneous epileptic-like discharges in transgenic mice.
abstract: ProNGF, the precursor of mature nerve growth factor (NGF), is the most abundant form of NGF in the brain. ProNGF and mature NGF differ significantly in their receptor interaction properties and in their bioactivity. ProNGF increases markedly in the cortex of Alzheimer's disease (AD) brains and proNGF\NGF imbalance has been postulated to play a role in neurodegeneration. However, a direct proof for a causal link between increased proNGF and AD neurodegeneration is lacking. In order to evaluate the consequences of increased levels of proNGF in the postnatal brain, transgenic mice expressing a furin cleavage-resistant form of proNGF, under the control of the neuron-specific mouse Thy1.2 promoter, were derived and characterized. Different transgenic lines displayed a phenotypic gradient of neurodegenerative severity features. We focused the analysis on the two lines TgproNGF#3 and TgproNGF#72, which shared learning and memory impairments in behavioral tests, cholinergic deficit and increased Aβ-peptide immunoreactivity. In addition, TgproNGF#3 mice developed Aβ oligomer immunoreactivity, as well as late diffuse astrocytosis. Both TgproNGF lines also display electrophysiological alterations related to spontaneous epileptic-like events. The results provide direct evidence that alterations in the proNGF/NGF balance in the adult brain can be an upstream driver of neurodegeneration, contributing to a circular loop linking alterations of proNGF/NGF equilibrium to excitatory/inhibitory synaptic imbalance and amyloid precursor protein (APP) dysmetabolism.
authors.affiliation: Neurotrophic Factors and Neurodegenerative Diseases Unit, EBRI-European Brain Research Institute, Rome, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Tiveron
authors.forename: L
authors.initials: L
authors.lastname: Fasulo
authors.forename: S
authors.initials: S
authors.lastname: Capsoni
authors.forename: F
authors.initials: F
authors.lastname: Malerba
authors.forename: S
authors.initials: S
authors.lastname: Marinelli
authors.forename: F
authors.initials: F
authors.lastname: Paoletti
authors.forename: S
authors.initials: S
authors.lastname: Piccinin
authors.forename: R
authors.initials: R
authors.lastname: Scardigli
authors.forename: G
authors.initials: G
authors.lastname: Amato
authors.forename: R
authors.initials: R
authors.lastname: Brandi
authors.forename: P
authors.initials: P
authors.lastname: Capelli
authors.forename: S
authors.initials: S
authors.lastname: D'Aguanno
authors.forename: F
authors.initials: F
authors.lastname: Florenzano
authors.forename: F
authors.initials: F
authors.lastname: La Regina
authors.forename: A
authors.initials: A
authors.lastname: Lecci
authors.forename: A
authors.initials: A
authors.lastname: Manca
authors.forename: G
authors.initials: G
authors.lastname: Meli
authors.forename: L
authors.initials: L
authors.lastname: Pistillo
authors.forename: N
authors.initials: N
authors.lastname: Berretta
authors.forename: R
authors.initials: R
authors.lastname: Nisticò
authors.forename: F
authors.initials: F
authors.lastname: Pavone
authors.forename: A
authors.initials: A
authors.lastname: Cattaneo
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D004195:Disease Models, Animal; D004827:Epilepsy / Q000503:physiopathology*; D006624:Hippocampus / Q000503:physiopathology; D006706:Homeostasis / Q000502:physiology*; D007859:Learning Disabilities / Q000503:physiopathology*; D008297:Male; D008569:Memory Disorders / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020932:Nerve Growth Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D019636:Neurodegenerative Diseases / Q000503:physiopathology*; D010641:Phenotype; D011498:Protein Precursors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D011498:Protein Precursors; C489226:pro-nerve growth factor, mouse; D020932:Nerve Growth Factor
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