The overall objective of this proposal is to investigate the nature of different signaling pathways involved in the etiopathogenesis of neurofibrillary degeneration of abnormally hyperphosphorylated tau, a hallmark brain lesion of Alzheimer disease (AD), Down syndrome, frontotemporal dementia, and other tauopathies, and employ this information to identify and diagnose the different subgroups of Alzheimer's disease. We postulate that more than one disease mechanism and signaling pathway are involved in producing AD pathology, and that various subgroups of this disease can be identified based on CSF levels of proteins associated with plaques and neurofibrillary tangles and of taus abnormally phosphorylated at various specific sites. To test this hypothesis we propose (1) to develop and validate ultrasensitive bienzyme-recycle ELISAs for various abnormal phosphorylation sites of tau. (2) To determine CSF levels of A?, ubiquitin and total tau, and tau phosphorylated at various specific sites using the assays developed in Aim #1 in AD and control cases, and identify subgroups of AD based on these data by cluster analysis. APOE genotype frequencies and clinical profiles of each cluster, including symptoms such as depression, hallucinations, hypokinesia, and rigidity, will be analyzed. The % sensitivity and % specificity of each phosphorylation site at appropriate cut-off points will be determined to evaluate its diagnostic potential. (3) To study the relationship of levels of soluble and aggregated A?1, 2, ubiquitin and various phosphotaus between CSF and brain in Alzheimer's disease. Levels of soluble and aggregated A?2, ubiquitin and various phosphotaus will be assayed by ELISA and radioimmuno-dot-blots in the frozen autopsied brains of AD cases from which lumbar CSFs are available. The levels of these markers in the brain will be correlated to the histopathological staging of the disease, and to the CSF levels of these markers. These studies will help (i) identify subgroups of AD based on CSF markers, (ii) provide a lead on the nature of signaling pathways involved in various subgroups, (iii) reveal the diagnostic potential of CSF levels of tau phosphorylated at different specific sites and (iv) identify the relationship of the CSF levels of A?, ubiquitin and tau to these markers in the brain and to the various histopathological stages of Alzheimer's disease. Better classification of AD at the molecular level and identification of biomarkers that represent the underlying disease process of various subtypes of the disease, in the long term, will lead to improved diagnosis and better defined treatment opportunities for AD and other tauopathies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG028538-05
Application #
8063476
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Miller, Marilyn
Project Start
2007-05-15
Project End
2013-04-30
Budget Start
2011-07-01
Budget End
2013-04-30
Support Year
5
Fiscal Year
2011
Total Cost
$320,870
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
Iqbal, Khalid; Bolognin, Silvia; Wang, Xiaochuan et al. (2013) Animal models of the sporadic form of Alzheimer's disease: focus on the disease and not just the lesions. J Alzheimers Dis 37:469-74
Wanka, Lukas; Iqbal, Khalid; Schreiner, Peter R (2013) The lipophilic bullet hits the targets: medicinal chemistry of adamantane derivatives. Chem Rev 113:3516-604
Iqbal, Khalid; Flory, Michael; Soininen, Hilkka (2013) Clinical symptoms and symptom signatures of Alzheimer's disease subgroups. J Alzheimers Dis 37:475-81
Wang, Jian-Zhi; Xia, Yi-Yuan; Grundke-Iqbal, Inge et al. (2013) Abnormal hyperphosphorylation of tau: sites, regulation, and molecular mechanism of neurofibrillary degeneration. J Alzheimers Dis 33 Suppl 1:S123-39
Iqbal, Khalid; Grundke-Iqbal, Inge (2011) Opportunities and challenges in developing Alzheimer disease therapeutics. Acta Neuropathol 122:543-9
Chalbot, Sonia; Zetterberg, Henrik; Blennow, Kaj et al. (2011) Blood-cerebrospinal fluid barrier permeability in Alzheimer's disease. J Alzheimers Dis 25:505-15
Chalbot, Sonia; Zetterberg, Henrik; Blennow, Kaj et al. (2010) Cerebrospinal fluid secretory Ca2+-dependent phospholipase A2 activity: a biomarker of blood-cerebrospinal fluid barrier permeability. Neurosci Lett 478:179-83
Iqbal, Khalid; Wang, Xiaochuan; Blanchard, Julie et al. (2010) Alzheimer's disease neurofibrillary degeneration: pivotal and multifactorial. Biochem Soc Trans 38:962-6
Iqbal, K; Liu, F; Gong, C-X et al. (2010) Tau in Alzheimer disease and related tauopathies. Curr Alzheimer Res 7:656-64
Alonso, Alejandra D; Di Clerico, John; Li, Bin et al. (2010) Phosphorylation of tau at Thr212, Thr231, and Ser262 combined causes neurodegeneration. J Biol Chem 285:30851-60

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