Alzheimer’s disease (AD) is a progressive neurodegenerative disorder pathologically characterized by deposition of ?-amyloid (A?)
cleavage product, soluble APP-?. These cleavage events are associated with elevated ?-secretase activity and enhanced hydrolysis of
tumor necrosis factor ?-converting enzyme, a primary candidate ?-secretase. As a validation of these findings in vivo, we treated Tg
APPswtransgenic mice overproducing A? with EGCG and found decreased A? levels and plaques associated with promotion of the
nonamyloidogenic ?-secretase proteolytic pathway. These data raise the possibility that EGCG dietary supplementation may provide
Amyloid precursor protein (APP) proteolysis is the fundamental
process for the production of ?-amyloid (A?) peptides impli-
cated in Alzheimer’s disease (AD) pathology (Golde et al., 2000;
Huse and Doms, 2000; Sambamurti et al., 2002; Funamoto et al.,
2004). APP proteolytic products arise from the coordinated ac-
tion of ?-, ?-, and ?-secretases. In the amyloidogenic pathway,
A? peptides are produced by the initial action of ?-secretase
(BACE) cleaveage, which creates an A?-containing C-terminal
fragment (CTF) known as ?-CTF or C99 (Sinha and Lieberburg,
1999; Yan et al., 1999). This proteolysis also generates an
extracellularly. Intracellularly, ?-CTF is then cleaved by a multi-
protein ?-secretase complex that results in generation of the A?
peptide and a smaller ?-CTF, also known as C57 (De Strooper et
al., 1998; Steiner et al., 1999). Conversely, in the nonamyloido-
genic pathway, APP is first cleaved at the ?-secretase site, which
?-CTF or C83 (Hooper and Turner, 2002), events that are indic-
ative of ?-secretase activity (Hooper and Turner, 2002). Because
of the limiting amount of APP in the cell and the failure to satu-
that the above-mentioned amyloidogenic and nonamyloido-
genic pathways compete for substrate in the process of APP pro-
teolysis (Gandhi et al., 2004). Therefore, it is often inferred that
extracellular elevation of sAPP-? (resulting from nonamyloido-
genic pathway activation) can be taken as indirect evidence of
inhibition of BACE and the associated amyloidogenic pathway.
However, because the extracellular secretion of these various
fragments can be regulated independently of APP cleavage, it is
important to fully characterize the effects of treatment on both
pathways concurrently before making inferences about underly-
ing mechanisms (Rossner et al., 2000).
Over the past decade, intense focus has been given to investi-
gating the processes of APP proteolysis and A? metabolism as
possible targets for AD therapy (Hardy and Selkoe, 2002). Vari-
ous synthetic and naturally occurring compounds have been an-
alyzed for their efficacy in the modulation of these pathological
This work was supported by the Johnnie B. Byrd Senior Alzheimer’s Center and Research Institute (J.T.) and
University of South Florida College of Medicine Faculty Start-Up funds (J.T.). T.T. was supported by a Ruth L.
tibodies against the C terminus of APP (369 antibody) and S. Gandy for providing the N2a cell lines that stably
TheJournalofNeuroscience,September21,2005 • 25(38):8807–8814 • 8807
ment leads to a reduction of A? levels in both SweAPP N2a cells
and Tg APPswmouse-derived primary neuronal cells. Further-
markedly increased in these cells after EGCG treatment, effects
that are correlated with elevated ?-secretase cleavage activity. To
demonstrate the in vivo therapeutic relevance of these observa-
and found a significant reduction in cerebral A? levels concom-
itant with reduced ?-amyloid plaques. In addition to intraperi-
toneal administration, intracerebroventricular injection of
EGCG into Tg APPswmice shows comparable reduction of cere-
bral A? levels associated with increased ?-secretase cleavage ac-
tivity, suggesting that the therapeutic effects of peripherally ad-
ministered EGCG are mainly derived from direct CNS action of
the compound. If A? pathology in this transgenic model is rep-
resentative of disease pathology in the clinical syndrome, then
EGCG administration to AD patients might be an effective pro-
phylactic strategy for reduction of cerebral amyloidosis.
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