Cell Calcium 34 (2003) 385–397 Neuronal and glial calcium signaling in Alzheimer’s disease Mark P. Mattson a,b,* , Sic L. Chan a a Laboratory of Neurosciences, National Institute on Aging, Gerontology Research Center 4F01, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA b Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA Received 10 May 2003; accepted 12 May 2003 Abstract Cognitive impairment and emotional disturbances in Alzheimer’s disease (AD) result from the degeneration of synapses and death of neurons in the limbic system and associated regions of the cerebral cortex. An alteration in the proteolytic processing of the amyloid precursor protein (APP) results in increased production and accumulation of amyloid -peptide (A) in the brain. A has been shown to cause synaptic dysfunction and can render neurons vulnerable to excitotoxicity and apoptosis by a mechanism involving disruption of cellular calcium homeostasis. By inducing membrane lipid peroxidation and generation of the aldehyde 4-hydroxynonenal, A impairs the function of membrane ion-motive ATPases and glucose and glutamate transporters, and can enhance calcium influx through voltage-dependent and ligand-gated calcium channels. Reduced levels of a secreted form of APP which normally regulates synaptic plasticity and cell survival may also promote disruption of synaptic calcium homeostasis in AD. Some cases of inherited AD are caused by mutations in presenilins 1 and 2 which perturb endoplasmic reticulum (ER) calcium homeostasis such that greater amounts of calcium are released upon stimulation, possibly as the result of alterations in IP 3 and ryanodine receptor channels, Ca 2+ -ATPases and the ER stress protein Herp. Abnormalities in calcium regulation in astrocytes, oligodendrocytes, and microglia have also been documented in studies of experimental models of AD, suggesting contributions of these alterations to neuronal dysfunction and cell death in AD. Collectively, the available data show that perturbed cellular calcium homeostasis plays a prominent role in the pathogenesis of AD, suggesting potential benefits of preventative and therapeutic strategies that stabilize cellular calcium homeostasis. © 2003 Elsevier Ltd. All rights reserved. Keywords: Amyloid; Apolipoprotein E; Apoptosis; Astrocytes; Microglia; Oligodendrocytes; Presenilin 1. Introduction There are currently more than 4 million Americans living with Alzheimer’s disease (AD), a devastating and always fatal neurodegenerative disorder characterized by progres- sive impairment of cognitive function and emotional dis- turbances. The disease process involves the degeneration of synapses and neurons in brain regions that play fundamental roles in learning and memory including the hippocampus, entorhinal cortex, basal forebrain, amygdala, frontal cortex, and inferior parietal cortex [1]. Two histological hallmarks of these brain regions of AD patients are the presence of aggre- gates of the amyloid -peptide (A) in the form of plaques, and the presence of filamentous intracellular aggregates of the microtubule-associated protein tau—the so-called neu- rofibrillary tangles. * Corresponding author. Tel.: +1-410-558-8463; fax: +1-410-558-8465. E-mail address: mattsonm@grc.nia.nih.gov (M.P. Mattson). Analyses of brain tissue from AD patients have provided evidence suggesting that alterations in cellular calcium homeostasis are associated with the neurodegenerative pro- cess. Levels of free and protein-bound calcium are increased in neurons containing neurofibrillary tangles as compared with tangle-free neurons [2]. Nixon and coworkers [3,4] have shown that levels of activated calcium-dependent pro- teases are also increased in neurofibrillary tangle-bearing neurons. The increased levels of calcium may precede tangle formation because levels of calcium/calmodulin-dependent protein kinase II are increased in neurons that are vulnera- ble to degeneration [5] and is associated with paired helical filaments [6]. In addition, levels of tissue transglutaminase (a calcium-activated enzyme) are increased in AD brain tis- sue [7], and can induce cross-linking of tau protein in vitro [8]. Studies of cultured neurons have provided evidence that elevated intracellular calcium levels, resulting from overac- tivation of glutamate receptors, can induce changes in the cytoskeleton similar to those seen in neurofibrillary tangles 0143-4160/$ – see front matter © 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S0143-4160(03)00128-3