Dysregulation of intracellular calcium signaling process has been critically implicated in the pathogenesis of Alzheimer's disease (AD). Notably, disrupting calcium homeostasis can markedly affect formation of each of the hallmark pathological lesions of this insidious disorder: b-amyloid, neurofibrillary tangles, and neuronal cell death. Moreover, calcium dyshomeostasis is an early and highly consistent alteration that occurs in certain earlyonset, autosomal dominant familial AD cases that are caused by mutations in the presenilin (PS1, PS2) genes. Mutations in the presenilin genes cause gain-of-function effects that lead to AD. Thus far, the two most consistent and pathologically significant disturbances associated with mutant presenilin molecules are alterations of proteolysis of proteins such as the b-amyloid precursor protein (APP) and disruption of intracellular calcium signaling processes. Surprisingly, the relationship between APP mismetabolism and calcium dyshomeostasis mediated by mutant presenilins has not been thoroughly investigated, which is the overarching objective of this research application. Toward this end, we propose 5 specific aims that will address the relationship between presenilin-mediated alterations of intracellular calcium signaling and APP proteolysis.
Aim 1 will establish if Ab is necessary for presenilin-mediated effects on calcium signaling, by studying cells that contain mutant PS1 but in which the APP gene is eliminated.
Aim 2 investigates whether increased A13 formation is sufficient to reproduce the effects of presenilin mutations on calcium signaling by studying primary neurons and cultured cells overexpressing APP.
Aim 3 uses cells derived from presenilin knock-out mice to establish the role of endogenous presenilins on calcium signaling.
Aim 4 will determine if y-secretase activity is required for the presenilin-mediated effects on calcium signaling by studying cells expressing dominant-negative presenilin mutations (i.e., mutants of the highly conserved transmembrane aspartate residues). Lastly, by manipulating calcium signaling and determining its effects on AB production, aim 5 will address whether the effects of presenilin mutations on calcium signaling are necessary and/or sufficient to increase Ab formation.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG017968-04
Application #
6753468
Study Section
Special Emphasis Panel (ZRG1-MDCN-2 (01))
Program Officer
Snyder, Stephen D
Project Start
2001-07-01
Project End
2006-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
4
Fiscal Year
2004
Total Cost
$321,480
Indirect Cost
Name
University of California Irvine
Department
Other Basic Sciences
Type
Schools of Arts and Sciences
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Kitazawa, Masashi; Cheng, David; Laferla, Frank M (2009) Chronic copper exposure exacerbates both amyloid and tau pathology and selectively dysregulates cdk5 in a mouse model of AD. J Neurochem 108:1550-60
Green, Kim N; Demuro, Angelo; Akbari, Yama et al. (2008) SERCA pump activity is physiologically regulated by presenilin and regulates amyloid beta production. J Cell Biol 181:1107-16
Green, K N; Smith, I F; Laferla, F M (2007) Role of calcium in the pathogenesis of Alzheimer's disease and transgenic models. Subcell Biochem 45:507-21
Smith, Ian F; Hitt, Brian; Green, Kim N et al. (2005) Enhanced caffeine-induced Ca2+ release in the 3xTg-AD mouse model of Alzheimer's disease. J Neurochem 94:1711-8
Kitazawa, Masashi; Oddo, Salvatore; Yamasaki, Tritia R et al. (2005) Lipopolysaccharide-induced inflammation exacerbates tau pathology by a cyclin-dependent kinase 5-mediated pathway in a transgenic model of Alzheimer's disease. J Neurosci 25:8843-53
Smith, Ian F; Green, Kim N; LaFerla, Frank M (2005) Calcium dysregulation in Alzheimer's disease: recent advances gained from genetically modified animals. Cell Calcium 38:427-37
Rissman, Robert A; Poon, Wayne W; Blurton-Jones, Mathew et al. (2004) Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology. J Clin Invest 114:121-30
Akbari, Yama; Hitt, Brian D; Murphy, M Paul et al. (2004) Presenilin regulates capacitative calcium entry dependently and independently of gamma-secretase activity. Biochem Biophys Res Commun 322:1145-52
Stutzmann, Grace E; Caccamo, Antonella; LaFerla, Frank M et al. (2004) Dysregulated IP3 signaling in cortical neurons of knock-in mice expressing an Alzheimer's-linked mutation in presenilin1 results in exaggerated Ca2+ signals and altered membrane excitability. J Neurosci 24:508-13
Kitazawa, Masashi; Yamasaki, Tritia R; LaFerla, Frank M (2004) Microglia as a potential bridge between the amyloid beta-peptide and tau. Ann N Y Acad Sci 1035:85-103

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