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From: TSS ()
Subject: Cellular prion protein regulates -secretase cleavage of the Alzheimer's amyloid precursor protein
Date: June 16, 2007 at 9:01 am PST

Published online before print June 15, 2007
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0609621104

Neuroscience

Cellular prion protein regulates -secretase cleavage of the Alzheimer's
amyloid precursor protein

( lipid raft | proteolysis | scrapie | glycosaminoglycan )

Edward T. Parkin *, Nicole T. Watt *, Ishrut Hussain , Elizabeth A. Eckman
¶, Christopher B. Eckman ¶, Jean C. Manson ||, Herbert N. Baybutt ||,
Anthony J. Turner *, and Nigel M. Hooper ***
*Proteolysis Research Group, Institute of Molecular and Cellular Biology,
Faculty of Biological Sciences, and Leeds Institute of Genetics, Health and
Therapeutics, University of Leeds, Leeds LS2 9JT, United Kingdom;
Neurodegeneration Research, Neurology and Gastrointestinal Centre of
Excellence for Drug Discovery, GlaxoSmithKline Research and Development
Limited, Third Avenue, Harlow, Essex CM19 5AW, United Kingdom; ¶Mayo Clinic,
Jacksonville, FL 32224; and ||Roslin Institute, Neuropathogenesis Unit,
Edinburgh EH9 3JF, United Kingdom

Edited by Stanley B. Prusiner, University of California, San Francisco, CA,
and approved May 10, 2007 (received for review October 30, 2006)

Proteolytic processing of the amyloid precursor protein (APP)
by -secretase, -site APP cleaving enzyme (BACE1), is the initial step in the
production of the amyloid (A) peptide, which is involved in the pathogenesis
of Alzheimer's disease. The normal cellular function of the prion protein
(PrPC), the causative agent of the transmissible spongiform encephalopathies
such as Creutzfeldt-Jakob disease in humans, remains enigmatic. Because both
APP and PrPC are subject to proteolytic processing by the same zinc
metalloproteases, we tested the involvement of PrPC in the proteolytic
processing of APP. Cellular overexpression of PrPC inhibited the -secretase
cleavage of APP and reduced A formation. Conversely, depletion of PrPC in
mouse N2a cells by siRNA led to an increase in A peptides secreted into the
medium. In the brains of PrP knockout mice and in the brains from two
strains of scrapie-infected mice, A levels were significantly increased. Two
mutants of PrP, PG14 and A116V, that are associated with familial human
prion diseases failed to inhibit the -secretase cleavage of APP. Using
constructs of PrP, we show that this regulatory effect of PrPC on
the -secretase cleavage of APP required the localization of PrPC to
cholesterol-rich lipid rafts and was mediated by the N-terminal polybasic
region of PrPC via interaction with glycosaminoglycans. In conclusion, this
is a mechanism by which the cellular production of the neurotoxic A is
regulated by PrPC and may have implications for both Alzheimer's and prion
diseases.


----------------------------------------------------------------------------
----

Author contributions: E.T.P., J.C.M., and N.M.H. designed research; E.T.P.,
N.T.W., I.H., E.A.E., C.B.E., and H.N.B. performed research; E.T.P., N.T.W.,
E.A.E., C.B.E., and N.M.H. analyzed data; I.H., E.A.E., and C.B.E.
contributed new reagents/analytic tools; and E.T.P., J.C.M., A.J.T., and
N.M.H. wrote the paper.

The authors declare no conflict of interest.

Present address: Department of Biological Sciences, Lancaster University,
Lancaster LA1 4YQ, United Kingdom.

**To whom correspondence should be addressed.

Nigel M. Hooper, E-mail: n.m.hooper@leeds.ac.uk

www.pnas.org/cgi/doi/10.1073/pnas.0609621104


http://www.pnas.org/cgi/content/abstract/0609621104v1?etoc


Alzheimer's and Transmissible Spongiform Encephalopathies

http://neurotalk.psychcentral.com/showthread.php?t=13175


Human and Animal Food Poisoning with Mad Cow a Slow Death

http://www.slowfoodforum.org/showthread.php?p=4042


Proof Mad Cow Is The Same
As Alzheimer's And CJD
How Many Of Them Are Really Mad Cow/vCJD/TSEs ???
How Can Government Claims Of Just 'One In A Million' Be Accurate
When CJD Is Not A Reportable Disease? And When The Elderly Do
Not Get Routinely Autopsied??

By Terry Singletary, Sr
12-27-03


http://www.rense.com/general46/proofa.html


More Evidence Mad Cow Same
As CJD And Alzheimer's
1-24-3

http://www.rense.com/general34/cjmd.htm


TSS





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