Slow Excitotoxicity in Alzheimer's Disease

Abstract

Abstract. Progress is being made in identifying possible pathogenic factors and novel genes in the development of Alzheimer's disease (AD). Many of these could contribute to 'slow excitotoxicity', defined as neuronal loss due to overexcitation as a consequence of decreased energy production due, for instance, to changes in insulin receptor signaling; or receptor abnormalities, such as tau-induced alterations in N-methyl-D-aspartate (NMDA) receptor phosphorylation. As a result, glutamate becomes neurotoxic at concentrations that normally show no toxicity. In AD, NMDA receptors are overexcited by glutamate in a tonic, rather than a phasic manner. Moreover, in prodromal AD subjects, functional MRI reveals an increase in neural network activities relative to baseline, rather than loss of activity. This may be an attempt to compensate for reduced number of neurons, or reflect ongoing slow excitotoxicity. This article reviews possible links between AD pathogenic factors such as A␤PP/A␤ and tau; novel risk genes including clusterin, phosphatidylinositol-binding clathrin assembly protein, complement receptor 1, bridging integrator 1, ATP-binding cassette transporter 7, membrane-spanning 4-domains subfamily A, CD2-associated protein, sialic acid-binding immunoglobulin-like lectin, and ephrin receptor A1; metabolic changes including insulin resistance and hypercholesterolemia; lipid changes including alterations in brain phospholipids, cholesterol and ceramides; glial changes affecting microglia and astrocytes; alterations in brain iron metallome and oxidative stress; and slow excitotoxicity. Better understanding of the possible molecular links between pathogenic factors and slow excitotoxicity could inform our understanding of the disease, and pave the way towards new therapeutic strategies for AD.

Identification of Cerebral Metal Ion Imbalance in the Brain of Aging Octodon degus

“…It is well established that increased Aβ can reduce the membrane potential, thus enhancing Ca 2+ influx, leading to an accumulation of Ca 2+ in cells, leading to excitotoxicity and cell death via apoptotic processes (Greenamyre, 1991; Harkany et al, 2000; Barger, 2004; Hynd et al, 2004; Tsai et al, 2005; Koutsilieri and Riederer, 2007). Increased oxidative stress may further interfere with Ca immobilization, leading to cell death via additional cytotoxic pathways (Esposito et al, 2013; Ong et al, 2013). It has been previously reported that Ca 2+ overload can modulate APP metabolism, and accelerate APP hydrolysis to generate more Aβ (Wang et al, 1994; Ye et al, 2010).…”

Glufosinate binds N-methyl-d-aspartate receptors and increases neuronal network activity in vitro

“…Disruption of this receptor has been associated with neurological disease including Alzheimer's disease (Hynd et al, 2004;Ong et al, 2013), multiple sclerosis (Kostic et al, 2013), autism (Essa et al, 2013), amyotrophic lateral sclerosis (Guo et al, 2003), and stroke (Hansen, 1995;Choi, 1998;Wang et al, 2010). Although human GLF poisoning cases are primarily from acute exposure, evidence suggests that GLF can produce chronic neurotoxic effects (Calas et al, 2008;Meme et al, 2009) or detrimentally impact the developing brain (Fujii et al, 1996;Watanabe, 1997).…”

Insights into the role of iron in immature rat model of hypoxic-ischemic brain injury

“…Previous studies have suggested that iron may contribute to nervous system development in children; an iron deficiency during infancy has been shown to affect the development of the nervous system, leading to poor intelligence, a lack of concentration, learning difficulties and various other symptoms (4,6). Conversely, other studies have reported an increased brain iron content in various adult demyelinating diseases, including Alzheimer's disease, Parkinson's disease, Huntington's chorea (7–9) and obstructive cerebral hemorrhage (10,11). Notably, iron chelation therapy, including deferoxamine, is able to markedly alleviate these diseases (12).…”