12 July 2001. It has become part of the standard lore on Alzheimer's
that a series of enzymes-dubbed α-, β-, and γ-secretase-successively chops away at the APP cell-surface protein, and that one
product of γ-secretase is the infamous Aβ-peptide. Yet why does
this orderly degradation of APP occur? The mystery only deepened last
year, when combined knockouts of APP and its homologues proved lethal,
suggesting the precursor protein must be doing something important
(Heber, et al.). Just what that something could be is the subject of a
July 6 paper in Science by Xinwei Cao and Thomas Sudhof of the Howard
Hughes Medical Institute at the University of Texas Southwestern Medical
Center in Dallas. The authors show that the less-studied product of
γ-secretase cleavage-an intracellular fragment comprising the
inner half of APP's transmembrane region plus its cytoplasmic tail-likely is involved in transcriptional activation.
"Our study provides a physiological reason for the processing of APP.
That has implications for AD, because once you know why it is cut you
can also look at why it is sometimes cut more and sometimes less," said
Sudhof. Gene transcription is tightly regulated by extracellular
signals, yet in sporadic AD there are no mutations that change any of
the known APP processing components. Possibly, sporadic AD develops
because the pathway that produces Aβ is dysregulated for many years,
The study also has implications for therapeutic attempts to block APP
processing. "For example, γ-secretase inhibition clearly is going to
have effects not only on Aβ production but also on nuclear signaling.
That could be good or bad," says Sudhof.
In their search for a function for APP processing, the researchers
pursued a trail laid down by notch, another cell-surface receptor that
substrate for γ-secretase. Following cleavage, its cytoplasmic tail
moves to the nucleus and regulates transcription there (Schroeter, et
al., and Struhl, et al.).
Cao created fusion proteins of APP with the DNA-binding domains of a
yeast and a bacterial transcription factor. These chimeric proteins allowed
Cao to measure if the APP cytoplasmic tail activates transcription of
reporter genes in transfected cell lines. The scientists found that the APP
fusion protein stimulated transcription only weakly on its own, but
transcription jumped more than 2,000-fold when the tail was bound to the
multi-domain adaptor protein Fe65. Fe65 is not specific to APP, but may
have a role in AD, much like Ras has many physiological binding partners
but plays a specific role in cancer, Sudhof says.
Moreover, Cao and Sudhof report that the APP cytoplasmic tail and Fe65
form a stable trimeric complex with Tip60, a histone acetyltransferase.
(These enzymes control access of transcriptional enzymes to genes by
modifying the packing density of the histone proteins wrapped around the
DNA). Tip60 itself is part of a nuclear protein complex that acts as a
general transcription factor.
Cao and Sudhof also report that all of Fe65's major domains are required
for transcriptional activation and that any mutation disrupting Fe65 binding
to the APP fragment or to Tip60 abolishes this function. Taken together, the
authors suggest that the complex of APP's cytoplasmic tail with Fe65 and
Tip60 directly acts in transcription. They add that this similarity
between APP and Notch supports the idea that presenilin-dependent
proteolysis functions as a general biological mechanism of
transcriptional regulation (Brown, et al.).
Although the in vitro experiments in the present study need to be repeated
with endogenous proteins, the work raises two important questions: Which
proteins regulate APP proteolysis, and which genes does the cytoplasmic APP
tail turn on or off? Stay tuned.-Gabrielle Strobel.
Reference:Cao X, Sudhof TC. A transcriptively active complex of app with fe65 and
histone acetyltransferase tip60. Science 2001 Jul 6;293(5527):115-20. Abstract