Oxidative stress and hypoxia-like injury cause Alzheimer-type molecular abnormalities in central nervous system neurons

Abstract

Neuronal loss and neuritic/cytoskeletal lesions (synaptic disconnection and proliferation of dystrophic neurites) represent major dementia-associated abnormalities in Alzheimer's disease (AD). This study examined the role of oxidative stress as a factor contributing to both the cell death and neuritic degeneration cascades in AD. Primary neuron cultures were treated with H2O2 (9-90 microM) or desferrioxamine (2-25 microM) for 24 h and then analyzed for viability, mitochondrial mass, mitochondrial function, and pro-apoptosis and sprouting gene expression. H2O2 treatment causes free-radical injury and desferrioxamine causes hypoxia-type injury without free radical generation. The H2O2-treated cells exhibited sustained viability but neurite retraction, impaired mitochondrial function, increased levels of the pro-apoptosis gene product CD95/Fas, reduced expression of N2J1-immunoreactive neuronal thread protein and synaptophysin, and reduced distribution of mitochondria in neuritic processes. Desferrioxamine treatment resulted in dose-dependent neuronal loss associated with impaired mitochondrial function, proliferation of neurites, and reduced expression of GAP-43, which has a role in path-finding during neurite outgrowth. The results suggest that oxidative stress can cause neurodegeneration associated with enhanced susceptibility to apoptosis due to activation of pro-apoptosis genes, neurite retraction (synaptic disconnection), and impaired transport of mitochondria to cell processes where they are likely required for synaptic function. In contrast, hypoxia-type injury causes neuronal loss with proliferation of neurites (sprouting), impaired mitochondrial function, and reduced expression of molecules required to form and maintain synaptic connections. Since similar abnormalities occur in AD, both oxidative stress and hypoxic injury can contribute to AD neurodegeneration.

Oxidative stress and modification of synaptic proteins in hippocampus after traumatic brain injury

“…Oxidative stress contributes to synaptic dysfunction and disconnection, with impaired mitochondrial transport to the synapses contributing to both neuronal death and neuritic degenerative cascades [15,16]. Exitotoxicity contributes to energy failure resulting in further oxidative stress by enhanced metabolism of excitatory amino acids, leading to secondary cascades of injuries following TBI [46].…”

“…These cascades implicate mitochondrial bioenergetic dysfunction, disruption of Ca 2 + homeostasis, and over production of ROS, adversely affecting synaptic functions and plasticity and neuronal loss [47]. CNS neurons injured by reactive radicals may be physically present but non-functional due to impaired energy metabolism, neuronal sickness, or impaired mitochondrial transport to the synaptic regions [15].…”

“…As a consequence of oxidative stress both the function and transport of mitochondrial to synaptic regions is impaired, decrease synaptic function [15,16], which results in neurodegeneration after brain injury [17,18]. A recent study reported that oxidative stress alters the function of PSD-95 by decreasing a voltage-gated potassium channel that is closely linked to the PSD [19], suggesting that synapse loss and replacement, known to occur following TBI [20], could be modulated by the levels of oxidative stress.…”

Aluminum Maltolate-Induced Toxicity in NT2 Cells Occurs Through Apoptosis and Includes Cytochrome c Release

“…Disrupted transport has been shown in AD (Cash et al, 2003;Praprotnik et al, 1996;Richard et al, 1989;Terry, 1996) and also amyotrophic lateral sclerosis (Williamson and Cleveland, 1999), however relatively few studies have examined this aspect of the disease (Kasa et al, 2000). Nonetheless, numerous factors implicated in AD including oxidative stress (de la Monte et al, 2000;Perry and Smith, 1997;Smith et al, 1995), APO e (Tesseur et al, 2000), and APP-L (Torroja et al, 1999) have all been shown to affect axonal transport. The observation that AbPP can serve as a kinesin cargo receptor (Kamal et al, 2000(Kamal et al, , 2001 as well as the inhibition of kinesin-dependent transport by tau overexpression (Ebneth et al, 1998;Stamer et al, 2002) should not be overlooked.…”

Oxidative Stress Does Not Predispose Neuronal Cells to Changes in G Protein Coupled (Opioid) Receptor Gene Expression in Cortical B50 Neurons in Culture

“…It has been observed that oxidative stress can cause neurodegeneration associated with enhanced susceptibility to apoptosis due to the activation of pro-apoptotic genes (Gibson and Huang 2002;Du et al 2012). Hypoxia-induced oxidative stress can cause neurite retraction leading to neurodegeneration and neuronal loss similar to that found in Alzheimer's disease (Banasiak et al 2000;de la Monte et al 2000;Yeh et al 2008;Prentice et al 2011;López-Hernández et al 2012).…”