? Neuronal?Ca2+?signaling?through?endoplasmic?reticulum?(ER)?localized?inositol?trisphosphate?(IP3R)?and? ryanodine?receptors?(RyR)?must?be?tightly?regulated?to?maintain?cell?viability,?both?acutely?and?over?the? lifetime?of?an?organism.??Exaggerated?ER?Ca2+?release?(up?to?4?fold)?has?been?associated?with?Alzheimer?disease? (AD)?mutations?expressed?in?cell?cultures?and?young?mice,?but?little?is?known?of?Ca2+?dysregulations?during? the?normal?and?pathological?aging?processes?using?adult?and?aged?models.?The?hypothesis?is?that?early? intracellular?Ca2+?dysregulation?represents?a?unique??calcium?opathy??that?contributes?to?later?progression?of? AD,?and?is?not?an?acclerated?component?of?normal?aging.??Aim?I?of?this?study?will?determine?and?differentiate? the?distinct?roles?of?neuronal?IP3?and?Ry?Ca2+?channels?in?a?non?transgenic?control?mouse?and?the?3xTg?AD? mouse?model?of?AD.??Aim?II?will?analyze?the?effects?of?age?and?AD?mutations?on?the?magnitude?of?the? exaggerated?ER?Ca2+?signals,?determine?downstream?effects?on?electrophsyiological?membrane?properties?and? synaptic?activity,?and?parse?the?contributions?of?PS1,?APP,?and?tau?mutations?by?comparing?3xTg?AD,? APP/Tau,?PS1KI?and?NonTg?control?mice.??Aim?III?will?seek?to?pharmacologically?reverse?the?exaggerated?ER? Ca2+?release?in?the?3xTg?AD?neurons?and?measure?effects?on?amyloid?plaque?deposition.??Likewise,?amyloid? plaques?will?be?cleared?in?older?3xTg?AD?mice?using?immunotherapy?techniques,?and?establish?if?there?is?a? functional?relationship?between?the?early?Ca2+?dysregulation?and?AD?histopathology.?These?studies?combine? electrophysiological?recording?in?brain?slices,?2?photon?Ca2+?imaging,?and?flash?photolysis?of?caged?compounds? from?control?(non?transgenic),?3xTg?AD,?APP/Tau?and?PS1KI??mice?at?young,?adult,?and?old?ages.? Immunohistochemical?techniques?will?be?used?to?map?and?quantify?changes?in?the?expression?of?IP3R?and?RyR? subtypes,?and?extent?of?AD?histopathology.??These?findings?will?elucidate?intracellular?signaling?changes?and? downstream?effects?on?neuronal?physiology?that?occur?both?in?normal?aging,?and?in?neurodegenerative? disorders?such?as?AD.??? Narrative: The objective of this study is to determine the functional relationship between early changes in neuronal Ca2+ signaling, and later pathophysiology associated with aging and Alzheimer's disease (AD). The results of this study will have scientific and clinical relevance by differentiating between neuronal signaling changes associated with normal aging and those associated with AD pathogenesis. Benefits to public health include the prospect for earlier AD diagnosis and novel therapeutic intervention, long before the onset of cognitive decline and irreversible histopathology.
|Briggs, Clark A; Schneider, Corinne; Richardson, Jill C et al. (2013) * amyloid peptide plaques fail to alter evoked neuronal calcium signals in APP/PS1 Alzheimer's disease mice. Neurobiol Aging 34:1632-43|
|Stutzmann, Grace E; Mattson, Mark P (2011) Endoplasmic reticulum Ca(2+) handling in excitable cells in health and disease. Pharmacol Rev 63:700-27|
|Demuro, Angelo; Parker, Ian; Stutzmann, Grace E (2010) Calcium signaling and amyloid toxicity in Alzheimer disease. J Biol Chem 285:12463-8|
|Goussakov, Ivan; Miller, Megan B; Stutzmann, Grace E (2010) NMDA-mediated Ca(2+) influx drives aberrant ryanodine receptor activation in dendrites of young Alzheimer's disease mice. J Neurosci 30:12128-37|