Alzheimer Disease: Stutzmann GE

Stutzmann GE. · Rosalind Franklin University of Medicine and Science, The Chicago Medical School, North Chicago, IL 60064, USA. · Neuroscientist. · Pubmed #17901262 No free full text.

Abstract: Alzheimer's disease (AD) is a fatal neurodegenerative disorder that has no known cure, nor is there a clear mechanistic understanding of the disease process itself. Although amyloid plaques, neurofibrillary tangles, and cognitive decline are late-stage markers of the disease, it is unclear how they are initially generated, and if they represent a cause, effect, or end phase in the pathology process. Recent studies in AD models have identified marked dysregulations in calcium signaling and related downstream pathways, which occur long before the diagnostic histopathological or cognitive changes. Under normal conditions, intracellular calcium signals are coupled to effectors that maintain a healthy physiological state. Consequently, sustained up-regulation of calcium may have pathophysiological consequences. Indeed, upon reviewing the current body of literature, increased calcium levels are functionally linked to the major features and risk factors of AD: ApoE4 expression, presenilin and APP mutations, beta amyloid plaques, hyperphosphorylation of tau, apoptosis, and synaptic dysfunction. In turn, the histopathological features of AD, once formed, are capable of further increasing calcium levels, leading to a rapid feed-forward acceleration once the disease process has taken hold. The views proposed here consider that AD pathogenesis reflects long-term calcium dysregulations that ultimately serve an enabling role in the disease process. Therefore, "Calcinists" do not necessarily reject betaAptist or Tauist doctrine, but rather believe that their genesis is associated with earlier calcium signaling dysregulations.

Stutzmann GE. · Department of Neurobiology and Behavior, 1146 McGaugh Hall, University of California-Irvine, Irvine, CA 92697, USA. · Neuroscientist. · Pubmed #15746379 No free full text.

Abstract: Ca(2+) ions subserve complex signaling roles in neurons, regulating functions ranging from gene transcription to modulation of membrane excitability. Ca(2+) ions enter the cytosol from extracellular sources, such as entry through voltage-gated channels, and by liberation from intracellular endoplasmic reticulum (ER) stores through inositol triphosphate (IP(3)) receptors and/or ryanodine (RyR) receptors. Disruptions of intracellular Ca(2+) signaling are proposed to underlie the pathophysiology of Alzheimer's disease (AD), and recent studies examining AD-linked mutations in the presenilin genes demonstrate enhanced ER Ca(2+) release in a variety of cell types and model systems. The development of transgenic AD mouse models provides a means to study the mechanisms and downstream effects of neuronal ER Ca(2+)-signaling alterations on AD pathogenesis and offers insight into potential novel therapeutic strategies. The author discusses recent findings in both the physiological functioning of the IP(3)-signaling pathway in neurons and the involvement of ERCa(2+) disruptions in the pathogenesis of AD.

Stutzmann GE, Smith I, Caccamo A, Oddo S, Parker I, Laferla F. · Department of Neuroscience, Rosalind Franklin University of Medicine and Science, The Chicago Medical School, 3333 Green Bay Road, North Chicago, IL 60064, USA. · Ann N Y Acad Sci. · Pubmed #17413028 No free full text.

Abstract: Intracellular Ca(2+) signaling involves Ca(2+) liberation through both inositol triphosphate and ryanodine receptors (IP(3)R and RyR). However, little is known of the functional interactions between these Ca(2+) sources in either neuronal physiology, or during Ca(2+) disruptions associated with Alzheimer's disease (AD). By the use of whole-cell recordings and 2-photon Ca(2+) imaging in cortical slices we distinguished between IP(3)R- and RyR-mediated Ca(2+) components in nontransgenic (non-Tg) and AD mouse models and demonstrate powerful signaling interactions between these channels. Ca(2+)-induced Ca(2+) release (CICR) through RyR contributed modestly to Ca(2+) signals evoked by photoreleased IP(3) in cortical neurons from non-Tg mice. In contrast, the exaggerated signals in 3xTg-AD and PS1(KI) mice resulted primarily from enhanced CICR through RyR, rather than through IP(3)R, and were associated with increased RyR expression levels. Moreover, membrane hyperpolarizations evoked by IP(3) in neurons from AD mouse models were even greater than expected simply from the exaggerated Ca(2+) signals, pointing to an increased coupling efficiency between cytosolic [Ca(2+)] and K(+) channel regulation. Our results highlight the critical roles of RyR-mediated Ca(2+) signaling in both neuronal physiology and pathophysiology, and point to presenilin-linked disruptions in RyR signaling as an important genetic factor in AD.

Stutzmann GE, Smith I, Caccamo A, Oddo S, Laferla FM, Parker I. · Department of Neurobiology and Behavior, University of California, Irvine, California 92697-4550, USA. · J Neurosci. · Pubmed #16687509 links to  free full text

Abstract: Neuronal Ca2+ signaling through inositol triphosphate receptors (IP3R) and ryanodine receptors (RyRs) must be tightly regulated to maintain cell viability, both acutely and over a lifetime. Exaggerated intracellular Ca2+ levels have been associated with expression of Alzheimer's disease (AD) mutations in young mice, but little is known of Ca2+ dysregulations during normal and pathological aging processes. Here, we used electrophysiological recordings with two-photon imaging to study Ca2+ signaling in nontransgenic (NonTg) and several AD mouse models (PS1KI, 3xTg-AD, and APPSweTauP301L) at young (6 week), adult (6 months), and old (18 months) ages. At all ages, the PS1KI and 3xTg-AD mice displayed exaggerated endoplasmic reticulum (ER) Ca2+ signals relative to NonTg mice. The PS1 mutation was the predominant "calciopathic" factor, because responses in 3xTg-AD mice were similar to PS1KI mice, and APPSweTauP301L mice were not different from controls. In addition, we uncovered powerful signaling interactions and differences between IP3R- and RyR-mediated Ca2+ components in NonTg and AD mice. In NonTg mice, RyR contributed modestly to IP3-evoked Ca2+, whereas the exaggerated signals in 3xTg-AD and PS1KI mice resulted primarily from enhanced RyR-Ca2+ release and were associated with increased RyR expression across all ages. Moreover, IP3-evoked membrane hyperpolarizations in AD mice were even greater than expected from exaggerated Ca2+ signals, suggesting increased coupling efficiency between cytosolic [Ca2+] and K+ channel regulation. We conclude that lifelong ER Ca2+ disruptions in AD are related to a modulation of RyR signaling associated with PS1 mutations and represent a discrete "calciumopathy," not merely an acceleration of normal aging.

Stutzmann GE, Caccamo A, LaFerla FM, Parker I. · Department of Neurobiology and Behavior, University of California, Irvine, Irvine, California 92697-4550, USA. · J Neurosci. · Pubmed #14724250 links to  free full text

Abstract: Disruptions in intracellular Ca2+ signaling are proposed to underlie the pathophysiology of Alzheimer's disease (AD), and it has recently been shown that AD-linked mutations in the presenilin 1 gene (PS1) enhance inositol triphosphate (IP3)-mediated Ca2+ liberation in nonexcitable cells. However, little is known of these actions in neurons, which are the principal locus of AD pathology. We therefore sought to determine how PS1 mutations affect Ca2+ signals and their subsequent downstream effector functions in cortical neurons. Using whole-cell patch-clamp recording, flash photolysis, and two-photon imaging in brain slices from 4-5-week-old mice, we show that IP3-evoked Ca2+ responses are more than threefold greater in PS1(M146V) knock-in mice relative to age-matched nontransgenic controls. Electrical excitability is thereby reduced via enhanced Ca2+ activation of K+ conductances. Action potential-evoked Ca2+ signals were unchanged, indicating that PS1(M146V) mutations specifically disrupt intracellular Ca2+ liberation rather than reduce cytosolic Ca2+ buffering or clearance. Moreover, IP3 receptor levels are not different in cortical homogenates, further suggesting that the exaggerated cytosolic Ca2+ signals may result from increased store filling and not from increased flux through additional IP3-gated channels. Even in young animals, PS1 mutations have profound effects on neuronal Ca2+ and electrical signaling: cumulatively, these disruptions may contribute to the long-term pathophysiology of AD.