Cell Death and Learning Impairment in Mice Caused by in Vitro Modified Pro-NGF Can Be Related to Its Increased Oxidative Modifications in Alzheimer Disease

Abstract

Pro-nerve growth factor (pro-NGF) is expressed at increased levels in Alzheimer's disease (AD)-affected brains and is able to induce cell death in cultures; however, the reasons for these phenomena remain elusive. Here we show that pro-NGF in human ADaffected hippocampus and entorhinal cortex is modified by advanced glycation and lipoxidation end-products in a stage-dependent manner. These modifications block pro-NGF processing to mature NGF, thus making the proneurotrophin especially effective in inducing apoptosis of PC12 cells in culture through the p75 neurotrophin receptor. The processing of advanced glycation and lipoxidation end-products in vitro modified recombinant human pro-NGF is severely impaired , as evidenced by Western blot and by examining its physiological functionality in cell cultures. We also report that modified recombinant human pro-NGF , as well as pro-NGF isolated from human brain affected by AD , cause impairment of learning tasks when administered intracerebroventricularly in mice , which correlates with AD-associated learning impairment. Taken together , the data we present here offer a novel pathway of ethiopathogenesis in AD caused by advanced glycation and lipoxidation end-products modification of pro-NGF. Oxidative stress occurs early in the progression of Alzheimer's disease (AD) even before the development of the pathological hallmarks, neurofibrillary tangles and senile plaques, depending on the stage of the disease and cerebral region. This is accompanied by degeneration of synapses and dendrites, and by cell death and neuronal loss.

Role of Neurotrophic Factor Alterations in the Neurodegenerative Process in HIV Associated Neurocognitive Disorders

“…A recent report suggested that pro-NGF observed in AD brains has undergone oxidative modifications by advanced glycation and lipid peroxidation that inhibit the processing of pro-NGF to its mature form, thereby resulting in an imbalance between the precursor and mature forms of the protein (Kichev et al, 2009). This altered processing favors the pro-apoptotic cascade mediated by enhanced levels of pro-NGF and is also consistent with the reduced levels of NGF and cholinergic degeneration observed in models of AD (Cuello and Bruno, 2007; Cuello et al, 2007; Cuello and Canneva, 2008; Cuello et al, 2010).…”

Mechanisms of disease

“…Some unexpected findings with respect to neurotrophin signaling in the nervous system are the ability of NGF and BDNF to induce apoptosis via p75NTR when Trk signaling is absent versus mediating survival when Trk signaling is present (Casaccia-Bonnefil et al, 1996;Friedman, 2000); and the ability of proNGF and proBDNF to bind p75NTR and form a high-affinity complex with the receptor sortilin that interacts with the prodomains of the proneurotrophins, thereby initiating apoptotic signaling cascades Jansen et al, 2007). In the latter, activation of the polyol pathway, a feature of the diabetic neuropathic state driven by excess glucose (Calcutt et al, 2009), leads to advanced glycation/lipoxidation end products inducing oxidative modifications that render the pro-NGF resistant to processing, thereby increasing its effectiveness as a pathologic ligand through its ability to induce apoptosis (Kichev et al, 2009). In the latter, activation of the polyol pathway, a feature of the diabetic neuropathic state driven by excess glucose (Calcutt et al, 2009), leads to advanced glycation/lipoxidation end products inducing oxidative modifications that render the pro-NGF resistant to processing, thereby increasing its effectiveness as a pathologic ligand through its ability to induce apoptosis (Kichev et al, 2009).…”

ProNGF\NGF imbalance triggers learning and memory deficits, neurodegeneration and spontaneous epileptic-like discharges in transgenic mice

“…At variance with the acute intracerebroventricular proNGF injections in rodents, 38,39 chronic exposure to high proNGF levels determines signs of AD neurodegeneration in transgenic mice. Although no abnormal tau pathology was found, a significant positivity for Ab and oligomeric Ab species was detected.…”