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 Ab-peptide immunoreactivity. In addition, TgproNGF#3 mice developed Ab 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.

A Pro-Nerve Growth Factor (proNGF) and NGF Binding Protein, α2-Macroglobulin, Differentially Regulates p75 and TrkA Receptors and Is Relevant to Neurodegeneration Ex Vivo and In Vivo

“…An association of increased ␣ 2 M and neurodegeneration was reported in animal models and in human diseases including glaucoma (4,14,23), diabetic retinopathy (21,22), and cognitive impairment (8,38). For example, in a normal eye the aqueous humor has ϳ1 to 10 nM ␣ 2 M, which is in part produced by glial/Muller cells in the retina (23).…”

“…However, in animal models of neurodegeneration and in human disease (4,8,14,(21)(22)(23)38), ␣ 2 M increases locally to Ͼ100 nM. Hence, it is likely that a significant portion of the proNGF and NGF in diseased or injured tissue is in the ␣ 2 M-bound state.…”

“…proNGF induces tumor necrosis factor alpha (TNF-␣) production by p75 NTR -expressing activated glia (4-6) and directly causes death in p75 NTR -expressing neurons (7)(8)(9). proNGF is proteolytically cleaved to produce mature NGF (2).…”

How Does p73 Cause Neuronal Defects?

“…Extrinsic factors including brain-derived neurotrophic factor (BDNF), neurotrophin 3, and nerve growth factor (NGF) play key roles in axon growth and dendritic morphology in cortical neurons [86]. The p75 neurotrophin receptor (p75NTR) is a member of the tumor necrosis factor receptor family that transduces signals from pro-and mature neurotrophins, including NGF [87][88][89]. p75NTR has multiple functions within the nervous system, ranging from neurite outgrowth and survival to apoptosis; these multiple functions are a reflection of the variety of ligands as well as the ability of p75NTR to interact with other receptors such as tyrosine kinase receptor B (TrkB) and sortilin [90][91][92][93].…”

Cystine knot growth factors and their functionally versatile proregions

“…Especially, in pathological scenarios and, in general, age-related processes, the pro-apoptotic processes predominate (Fahnestock et al, 2001;Al-Shawi et al, 2007;Jansen et al, 2007;Nakamura et al, 2007;Yune et al, 2007;Volosin et al, 2008;Tauris et al, 2011). A mouse model, in which the balance was shifted towards elevated levels of proNGF through the expression of an non-cleavable pro-form, revealed learning and memory defects due to enhanced neurodegeneration (Tiveron et al, 2013).…”