? 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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG030205-05
Application #
8300832
Study Section
Special Emphasis Panel (ZRG1-MDCN-P (02))
Program Officer
Refolo, Lorenzo
Project Start
2008-08-15
Project End
2013-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$270,375
Indirect Cost
$94,807
Name
Rosalind Franklin University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
069501252
City
North Chicago
State
IL
Country
United States
Zip Code
60064
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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