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Distinct sites of intracellular production for Alzheimer's disease Abeta40/42 amyloid peptides
Tobias Hartmann1, Sophie C. Bieger2, Babara Brhl3, Pentti J. Tienari4, Nobuo Ida1, David Allsop5, Gareth W. Roberts5,
Colin L. Masters6, Carlos G. Dotti7, Klaus Unsicker3 & Konrad Beyreuther1
1Zentrum fr Molekulare Biologie der Universit„t Heidelberg (ZMBH), INF282, D-69120 Heidelberg, Germany 2Department
of Anatomy & Neurobiology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4H2 3Department of Anatomy & Cell
Biology, INF307, University of Heidelberg, D-69120 Heidelberg, Germany 4Department of Neurology, University of
Helsinki, Haartmaninkatu, Fin-00290 Helsinki, Finland 5SmithKline Beecham, New Frontier Science Park, Harlow, Essex
CM19 5AW, UK 6Department of Pathology, University of Melbourne, Parkville, Victoria 3052, Australia 7European
Molecular Biology Laboratory (EMBL), Mayerhofstrasse 1, D-69012 Heidelberg, Germany Correspondence should be
addressed to T.H.
The Alzheimer amyloid precursor protein (APP) is cleaved by several proteases, the most studied, but
still unidentified ones, are those involved in the release of a fragment of APP, the amyloidogenic
beta-protein Abeta. Proteolysis by gamma-secretase is the last processing step resulting in release of
Abeta. Cleavage occurs after residue 40 of Abeta [Abeta(1-40)], occasionally after residue 42
[Abeta(1-42)]. Even slightly increased amounts of this Abeta(1-42) might be sufficient to cause
Alzheimer's disease (AD) (reviewed in ref. 1, 2). It is thus generally believed that inhibition of this
enzyme could aid in prevention of AD. Unexpectedly we have identified in neurons the endoplasmic
reticulum (ER) as the site for generation of Abeta(1-42) and the trans-Golgi network (TGN) as the site
for Abeta(1-40) generation. It is interesting that intracellular generation of Abeta seemed to be unique
to neurons, because we found that nonneuronal cells produced significant amounts of Abeta(1-40) and
Abeta(1-42) only at the cell surface. The specific production of the critical Abeta isoform in the ER of
neurons links this compartment with the generation of Abeta and explains why primarily ER localized
(mutant) proteins such as the presenilins3 could induce AD. We suggest that the earliest event taking
place in AD might be the generation of Abeta(1-42) in the ER.<<
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