The broad, long-term objective of the project is to understand the importance of neuronal calcium (Ca2+) signaling in pathogenesis of Alzheimer's disease (AD). Presenilins are transmembrane proteins localized to endoplasmic reticulum (ER). Missense mutations in presenilins account for 40% of familial AD (FAD) cases. Many FAD mutations in presenilins have been also linked to abnormal endoplasmic reticulum (ER) calcium (Ca2+) signaling. The main aim of the current proposal is to understand the connection between mutations in presenilins, dysregulation of neuronal ER Ca2+ signaling and synaptic loss and dysfunction in AD. Specifically, we will focus on testing the novel hypothesis that defects in ER Ca2+ signaling may lead to destabilization of "mushroom spines" widely considered to be physical units for memory storage by attacking these aims:. 1. To investigate the importance of postsynaptic store-operated calcium (SOC) entry pathway downregulation in loss of mature synaptic spines in AD. Our preliminary data suggest that the increase in neuronal ER Ca2+ levels leads to a compensatory downregulation of neuronal store-operated Ca2+ entry pathway (nSOC). We discovered that the downregulation of nSOC occurs due to reduced expression of STIM2 protein, a master regulator of nSOC. We propose that reduction in synaptic nSOC causes destabilization and eventual elimination of mushroom spines, leading to loss of memories in FAD and aging brains. This hypothesis will be tested in experiments with PS1-FAD mouse model and STIM2 conditional knockout mouse model. 2. To investigate the connection between dysregulation of neuronal activity and destabilization of LTP- induced mature synaptic spines in AD. Our preliminary data indicate that appropriate pattern of neuronal activity is criticl for maintenance of mature "mushroom spines". We further discovered that abnormal ER Ca2+ signaling causes disruption of this pattern in PS1-FAD neurons. We will perform a series of experiments aimed at dissecting the connection between ER Ca2+ homeostasis, neuronal activity pattern and stability of mushroom spines in AD neurons. We will evaluate a crucial role of intracellular Ca2+ stores and SK family of Ca2+-activated potassium channels in this process. 3. To analyze the cross-talk of amyloid and calcium pathways for AD pathogenesis. Abeta42 oligomers influence neuronal Ca2+ signaling and neuronal activity via variety of pathways. In this aim we will investigate if some of the Ca2+-related targets and pathways explored in SA1 and SA2 may also apply to models of amyloid synaptotoxicity. These experiments will be performed with in vitro model of Abeta42 synaptotoxicity and with recently generated APP-KI mouse model of AD.

Public Health Relevance

The proposed project will have direct and immediate relevance for public health. Alzheimer's disease (AD) is a major cause of dementia in the elderly and an enormous health problem. The experiments described in the grant are aimed at testing specific hypothesis regarding pathogenesis of AD and will provide information critical for eventual development of the cure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS080152-02
Application #
8720077
Study Section
Special Emphasis Panel (ZRG1-MDCN-N (03))
Program Officer
Corriveau, Roderick A
Project Start
2013-08-15
Project End
2018-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$454,522
Indirect Cost
$168,659
Name
University of Texas Sw Medical Center Dallas
Department
Physiology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Sun, Suya; Zhang, Hua; Liu, Jie et al. (2014) Reduced synaptic STIM2 expression and impaired store-operated calcium entry cause destabilization of mature spines in mutant presenilin mice. Neuron 82:79-93
Popugaeva, Elena; Bezprozvanny, Ilya (2014) Can the calcium hypothesis explain synaptic loss in Alzheimer's disease? Neurodegener Dis 13:139-41
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Bezprozvanny, Ilya; Hiesinger, Peter Robin (2013) The synaptic maintenance problem: membrane recycling, Ca2+ homeostasis and late onset degeneration. Mol Neurodegener 8:23