The long-term goal of this proposal is to understand the mechanisms involved in the fibrillogenesis of amyloid beta-protein (Abeta). This will be achieved by studying the formation of hydrophobic domain by aggregated / fibrillar amyloid beta-protein, and gelsolin-mediated inhibition of Abeta fibrillization. We have developed a diphenylhexatriene (DPH) fluorescence spectroscopic method for measuring fibrillar (f) Abeta, that is based on the hydrophobic domain formation by fAbeta. We hypothesize that formation of hydrophobic domain is the first event in Abeta fibrillogenesis, which may be prerequisite for nucleus formation. We propose that measuring Abeta fibrillization by DPH fluorescence spectroscopy may be an ideal tool to study the hydrophobic domain formation (nucleus) and its growth thereafter. We have reported earlier that extracellular gelsolin inhibits Abeta fibrillogenesis, and solubilizes Abeta fibrils. The regulation of Abeta fibrillogenesis by gelsolin will be studied by investigating the effect of gelsolin on hydrophobic domain formation and growth of Abeta filaments, binding-site of Abeta on gelsolin, neuroprotective action of gelsolin against Abeta toxicity, and comparing the gelsolin content in the blood and cerebrospinal fluid of patients with Alzheimer's disease, other neurological diseases, and age-matched non-demented control subjects. If our hypotheses are correct, then we will be able to detect the early stages of hydrophobic domain formation by fibrillar Abeta, and establish role of gelsolin / gelsolin-peptide(s) in the inhibition of Abeta fibrillogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG020992-02
Application #
6893980
Study Section
Special Emphasis Panel (ZRG1-CNNT (02))
Program Officer
Snyder, Stephen D
Project Start
2004-05-15
Project End
2007-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
2
Fiscal Year
2005
Total Cost
$170,459
Indirect Cost
Name
Institute for Basic Research in Dev Disabil
Department
Type
DUNS #
167205090
City
Staten Island
State
NY
Country
United States
Zip Code
10314
Ji, Lina; Chauhan, Ved; Mehta, Pankaj et al. (2010) Relationship between proteolytically cleaved gelsolin and levels of amyloid-? protein in the brains of Down syndrome subjects. J Alzheimers Dis 22:609-17
Ji, Lina; Chauhan, Abha; Chauhan, Ved (2010) Upregulation of cytoplasmic gelsolin, an amyloid-beta-binding protein, under oxidative stress conditions: involvement of protein kinase C. J Alzheimers Dis 19:829-38
Ji, Lina; Chauhan, Abha; Chauhan, Ved (2010) Calcium induces expression of cytoplasmic gelsolin in SH-SY5Y and HEK-293 cells. Neurochem Res 35:1075-82
Ji, Lina; Chauhan, Abha; Wegiel, Jerzy et al. (2009) Gelsolin is proteolytically cleaved in the brains of individuals with Alzheimer's disease. J Alzheimers Dis 18:105-11
Ji, Lina; Chauhan, Abha; Muthaiyah, Balu et al. (2009) Gelsolin levels are increased in the brain as a function of age during normal development in children that are further increased in Down syndrome. Alzheimer Dis Assoc Disord 23:319-22
Ji, Lina; Chauhan, Abha; Brown, W Ted et al. (2009) Increased activities of Na+/K+-ATPase and Ca2+/Mg2+-ATPase in the frontal cortex and cerebellum of autistic individuals. Life Sci 85:788-93
Chauhan, Ved; Ji, Lina; Chauhan, Abha (2008) Anti-amyloidogenic, anti-oxidant and anti-apoptotic role of gelsolin in Alzheimer's disease. Biogerontology 9:381-9
Ji, Lina; Chauhan, Abha; Chauhan, Ved (2008) Cytoplasmic gelsolin in pheochromocytoma-12 cells forms a complex with amyloid beta-protein. Neuroreport 19:463-6
Chander, Harish; Chauhan, Abha; Chauhan, Ved (2007) Binding of proteases to fibrillar amyloid-beta protein and its inhibition by Congo red. J Alzheimers Dis 12:261-9
Chander, Harish; Chauhan, Abha; Wegiel, Jerzy et al. (2006) Binding of trypsin to fibrillar amyloid beta-protein. Brain Res 1082:173-81

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