Misregulation of transcription of theB-amyloid precursor protein (APP) gene is implicated in the Pathogenesis of Alzheimer's disease (AD). Several early studies indicated that the APP gene expression might be increased in AD brains. That increases in the APP expression can lead to AD is strongly suggested by its high incidence in Down's syndrome patients with three copies of the gene. AD is a complex disorder with potentially multiple triggers. It is quite possible that disturbance in the transcriptional regulation of APP affects a subset of AD patients. Alternatively, failure to observe consistently a detectable increase in APP mRNA in post-mortem brains may be due to a transient over expression of APP, which may lead to nucleation of amyloid plaques. Our hypothesis is that the APP regulatory pathways play a critical role in AD pathogenesis. Our long-term goal is to study the transcriptional control of the APP gene. We have recently cloned and characterized a 7.9 kb APP promoter region. Here we will examine the role of the upstream regulatory elements (URE) on APP promoter activity and in late-onset AD. This proposal is based on our novel finding that a -75 to +104 bp region regulates APP promoter activity in a cell-type specific manner.
The specific aims are: 1) To determine the coredomain of APP promoter that is essential for its activity and indelibility. Certain upstream regulatory regions that confer basic promoter activity in neurons and astrocytes may respond to activation by growth factors and cytokines, which are produced by activated macrophages during the inflammatory response in AD. Functional characterization of the regulatory regions will be done by a serial deletion strategy and DNA transfection in cell lines and primary cultures. 2) To identify whether URE interacts with a cell type specific nuclear protein. We will study how the specific upstream region interacts with a cell type-specific factor in neurons and astrocytes and how this interaction will be affected in the presence of cytokines and growth factors. 3) To determine the role of URE in the developmental and disease state. Differential effects of the promoter region in cell types might suggest a role for URE during development and differentiation. We plan to examine the levels of URE-binding factor in developmental rat brains, normal and AD brains. 4) To determine the genetic variability of the regulatory region in AD. The genetic variability of the regulatory region may be important for late-onset AD sporadic subjects. We propose to screen genomic DNA for 'promoter elements' and to compare the 'promoter binding factors' in control and AD subjects. 5) To manipulate promoter activity in cell culture. We plan to modify the specific regulatory effect of the APP promoter by in vivo competition experiment and using the antisense oligodeoxynucleotide strategy. Finally, we will correlate promoter studies with levels of APP and AB in control and AD subjects. Understanding the complex interplay between the promoter domains and the transcription factors may suggest novel methods for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG018379-02
Application #
6372515
Study Section
Special Emphasis Panel (ZRG1-BDCN-1 (01))
Program Officer
Snyder, D Stephen
Project Start
2000-09-01
Project End
2005-08-31
Budget Start
2001-09-01
Budget End
2002-08-31
Support Year
2
Fiscal Year
2001
Total Cost
$294,227
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Psychiatry
Type
Schools of Medicine
DUNS #
005436803
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Ray, Balmiki; Sokol, Deborah K; Maloney, Bryan et al. (2016) Finding novel distinctions between the sAPP?-mediated anabolic biochemical pathways in Autism Spectrum Disorder and Fragile X Syndrome plasma and brain tissue. Sci Rep 6:26052
Kim, Eunhee; Woo, Moon-Sook; Qin, Luye et al. (2015) Daidzein Augments Cholesterol Homeostasis via ApoE to Promote Functional Recovery in Chronic Stroke. J Neurosci 35:15113-26
Erickson, Craig A; Ray, Balmiki; Maloney, Bryan et al. (2014) Impact of acamprosate on plasma amyloid-? precursor protein in youth: a pilot analysis in fragile X syndrome-associated and idiopathic autism spectrum disorder suggests a pharmacodynamic protein marker. J Psychiatr Res 59:220-8
Perez, Felipe P; Bose, David; Maloney, Bryan et al. (2014) Late-onset Alzheimer's disease, heating up and foxed by several proteins: pathomolecular effects of the aging process. J Alzheimers Dis 40:1-17
Reale, Marcella; Di Nicola, Marta; Velluto, Lucia et al. (2014) Selective acetyl- and butyrylcholinesterase inhibitors reduce amyloid-? ex vivo activation of peripheral chemo-cytokines from Alzheimer's disease subjects: exploring the cholinergic anti-inflammatory pathway. Curr Alzheimer Res 11:608-22
Long, Justin M; Ray, Balmiki; Lahiri, Debomoy K (2014) MicroRNA-339-5p down-regulates protein expression of ?-site amyloid precursor protein-cleaving enzyme 1 (BACE1) in human primary brain cultures and is reduced in brain tissue specimens of Alzheimer disease subjects. J Biol Chem 289:5184-98
Counts, Scott E; Lahiri, Debomoy K (2014) Overview of immunotherapy in Alzheimer's disease (AD) and mechanisms of IVIG neuroprotection in preclinical models of AD. Curr Alzheimer Res 11:623-5
Greig, Nigel H; Tweedie, David; Rachmany, Lital et al. (2014) Incretin mimetics as pharmacologic tools to elucidate and as a new drug strategy to treat traumatic brain injury. Alzheimers Dement 10:S62-75
Lahiri, Debomoy K; Maloney, Bryan; Long, Justin M et al. (2014) Lessons from a BACE1 inhibitor trial: off-site but not off base. Alzheimers Dement 10:S411-9
Yu, Qian-Sheng; Reale, Marcella; Kamal, Mohammad A et al. (2013) Synthesis of the Alzheimer drug Posiphen into its primary metabolic products (+)-N1-norPosiphen, (+)-N8-norPosiphen and (+)-N1, N8-bisnorPosiphen, their inhibition of amyloid precursor protein, ?-Synuclein synthesis, interleukin-1? release, and cholinergi Antiinflamm Antiallergy Agents Med Chem 12:117-28

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