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.
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Abbreviations
- NGF:
-
nerve growth factor
- AD:
-
Alzheimer’s disease
- Aβ:
-
amyloid-β
- APP:
-
amyloid precursor protein
- IRES:
-
internal ribosome entry site sequence
- EGFP:
-
green fluorescent protein
- CTX:
-
cortex
- WT:
-
wild type
- AA:
-
active avoidance test
- ORT:
-
object recognition test
- MWM:
-
Morris water maze test
- ChAT:
-
choline acetyltransferase
- BFCN:
-
basal forebrain cholinergic neurons
- HP:
-
hippocampus
- BF:
-
basal forebrain
- GFAP:
-
glial fibrillar acidic protein
- ScFv:
-
single-chain antibody fragment
- AβO:
-
Aβ oligomers
- EC:
-
entorhinal cortex
- LTP:
-
long-term potentiation
- IP:
-
immunoprecipitation
- Tg:
-
transgenic
- DS:
-
Down syndrome
- E\I:
-
excitatory\inhibitory
- MCI:
-
mild cognitive impairment
- MMP:
-
matrix metalloproteinase
- DG:
-
dentate gyrus
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Acknowledgements
This paper is dedicated to our beloved friend and coauthor Cecilia Tiveron, who made a crucial contribution to this project before she passed away on 17 December 2010, as a tribute to her enthusiasm and dedication to science and to her friendship. We also dedicate the paper to Professor Rita Levi-Montalcini, Nobel Laureate founder of the EBRI institute, tireless and enthusiastic example for all of us. This work was funded by EU FP6 MEMORIES Project (no. 037831), Telethon grant no. GGP05234, the Italian Institute of Technology (IIT), the Italian Ministry of Higher Education and Scientific Research (FIRB no. RBAP10L8TY) and Fondazione Roma. We thank Domenico Vignone for valuable help with the immunohistochemistry experiments and Andrea Urbani for advise on the mass spectrometry analysis.
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Tiveron, C., Fasulo, L., Capsoni, S. et al. ProNGF\NGF imbalance triggers learning and memory deficits, neurodegeneration and spontaneous epileptic-like discharges in transgenic mice. Cell Death Differ 20, 1017–1030 (2013). https://doi.org/10.1038/cdd.2013.22
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DOI: https://doi.org/10.1038/cdd.2013.22
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