Slow Excitotoxicity in Alzheimer's Disease

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 beta PP/A beta 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.