Amyloid precursor protein (APP) proteolysis is the fundamental process for the production of ?-amyloid (A?) peptides implicated in Alzheimer's disease (AD) pathology. Since 1-secretase cleaves within the A? peptide domain, its activation may have the double advantage of not only precluding the neurotoxic A? peptide formation, but also generating the putatively neuroprotective sAPP-?. Thus, it would appear highly advantageous to shift APP cleavage from the amyloidogenic 2-secretase to the non-amyloidogenic ?- secretase cleavage. Our recent data show that green tea derived (-)-epigallocatechin-3-gallate (EGCG) reduces A? peptide generation in """"""""Swedish"""""""" mutant APP-overexpressing primary neurons (Tg2576 mouse- derived primary neuronal cells) and neuron-like cells (SweAPP N2a cells). In concert with these observations, we found that EGCG markedly activates cleavage of 1-CTF and elevates sAPP-1 (Rezai-Zadeh et al., 2005). These cleavage events are associated with elevated 1-secretase cleavage activity and enhanced activation of a disintegrin and metalloprotease 10 (ADAM10), a primary candidate for 1-secretase (Obregon et al., 2006). As a validation of these findings in vivo, we treated A?-overproducing Tg2576 transgenic mice intraperitoneally with EGCG and found significantly decreased A? levels/plaques in the brain (Rezai-Zadeh et al., 2005). These effects are associated with promotion of the non-amyloidogenic 1-secretase proteolytic pathway. In this proposal, we will evaluate EGCG's therapeutic effect on reducing cerebral amyloidosis and improving cognitive impairment in a transgenic mouse model of AD via an oral administration.
In Aim 1, we will employ oral administration of green tea-EGCG (TeaMemTM) to Tg2576 mice before (prophylactic treatment group) and after (therapeutic treatment group) the development of AD-like pathology. Groups of untreated non-transgenic littermates compared to the transgenic treatment groups. Oral administration of TeaMemTM or vehicle (H2O) to Tg2576 mice will be performed for 6 months. Following the administration, we will sacrifice these mice at several ages to examine histologic and biochemical endpoints. Furthermore, following more long-term TeaMemTM administration, cognitive testing will be done prior to euthanasia.
In Aim 2, we will employ oral administration of TeaMemTM in the presence or absence of piperine to Tg2576 mice before (prophylactic treatment group) and after (therapeutic treatment group) the development of AD-like pathology for 6 months. In this study, we plan to evaluate two time points comparing TeaMemTM alone to TeaMemTM plus piperine. Groups will be compared by their effects on reducing AD-like pathology and opposing behavioral impairment. These studies could lay the foundation for AD clinical trials with pure TeaMemTM or/and piperine in the near future.

Public Health Relevance

In this proposal, we will fully characterize the effect of green tea derived EGCG (TeaMemTM) on increasing non-amyloidogenic 1-secretase cleavage and evaluate its therapeutic effect on reducing cerebral amyloidosis and being beneficial to cognitive impairment in a transgenic mouse model of Alzheimer's disease (AD). These studies will lay the foundation for AD clinical trials with pure TeaMemTM or/and piperine (an alkaloid derived from black pepper) in the near future. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
Project #
1R43AT004871-01
Application #
7537870
Study Section
Special Emphasis Panel (ZRG1-BDCN-A (11))
Program Officer
Pontzer, Carol H
Project Start
2008-09-30
Project End
2010-03-31
Budget Start
2008-09-30
Budget End
2010-03-31
Support Year
1
Fiscal Year
2008
Total Cost
$106,987
Indirect Cost
Name
Natural Therapeutics, Inc.
Department
Type
DUNS #
163511780
City
Tampa
State
FL
Country
United States
Zip Code
33612
Brown, Lecia A M; Jin, Jingji; Ferrell, Darren et al. (2014) Efavirenz promotes ?-secretase expression and increased A?1-40,42 via oxidative stress and reduced microglial phagocytosis: implications for HIV associated neurocognitive disorders (HAND). PLoS One 9:e95500
Jin, Jingji; Lam, Lucy; Sadic, Edin et al. (2012) HIV-1 Tat-induced microglial activation and neuronal damage is inhibited via CD45 modulation: A potential new treatment target for HAND. Am J Transl Res 4:302-15
Giunta, Brian; Hou, Houyan; Zhu, Yuyan et al. (2010) Fish oil enhances anti-amyloidogenic properties of green tea EGCG in Tg2576 mice. Neurosci Lett 471:134-8
Fernandez, Jamie Winderbaum; Rezai-Zadeh, Kavon; Obregon, Demian et al. (2010) EGCG functions through estrogen receptor-mediated activation of ADAM10 in the promotion of non-amyloidogenic processing of APP. FEBS Lett 584:4259-67
Smith, Adam; Giunta, Brian; Bickford, Paula C et al. (2010) Nanolipidic particles improve the bioavailability and alpha-secretase inducing ability of epigallocatechin-3-gallate (EGCG) for the treatment of Alzheimer's disease. Int J Pharm 389:207-12
Giunta, Brian; Rezai-Zadeh, Kavon; Tan, Jun (2010) Impact of the CD40-CD40L dyad in Alzheimer's disease. CNS Neurol Disord Drug Targets 9:149-55