Neuronal and glial calcium signaling in Alzheimer’s disease

By. CBHI Research Team

Mark P. Mattson a,b,∗, Sic L. Chana 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. Analteration 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 IP3 and ryanodine receptor channels, Ca2+-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.

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 progressive impairment of cognitive function and emotional disturbances. 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 aggregates 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 neurofibrillary tangles.
∗ Corresponding author. Tel.: +1-410-558-8463; fax: +1-410-558-8465. E-mail address: mattsonm@grc.nia.nih.gov (M.P. Mattson).