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High-Level Neuronal Expression of A 1-42 in
Wild-Type Human Amyloid Protein Precursor Transgenic Mice:
Synaptotoxicity without Plaque Formation
Lennart
Mucke1, 2, 3,
Eliezer
Masliah4,
Gui-Qiu
Yu1,
Margaret
Mallory4,
Edward M.
Rockenstein4,
Gwen
Tatsuno5,
Kang
Hu5,
Dora
Kholodenko5,
Kelly
Johnson-Wood5, and
Lisa
McConlogue5
1 Gladstone Institute of Neurological Disease,
2 Department of Neurology, and 3 Neuroscience
Program, University of California, San Francisco, California
94141-9100, 4 Departments of Neurosciences and Pathology,
University of California at San Diego, La Jolla, California 92093-0624, and 5 Elan Pharmaceuticals, South San Francisco, California
94080
Amyloid plaques are a neuropathological hallmark of Alzheimer's
disease (AD), but their relationship to neurodegeneration and dementia
remains controversial. In contrast, there is a good correlation in AD
between cognitive decline and loss of synaptophysin-immunoreactive (SYN-IR) presynaptic terminals in specific brain regions. We used expression-matched transgenic mouse lines to compare the effects of
different human amyloid protein precursors (hAPP) and their products on
plaque formation and SYN-IR presynaptic terminals. Four distinct
minigenes were generated encoding wild-type hAPP or hAPP carrying
mutations that alter the production of amyloidogenic A peptides. The
platelet-derived growth factor chain promoter was used to
express these constructs in neurons. hAPP mutations associated
with familial AD (FAD) increased cerebral A1-42 levels,
whereas an experimental mutation of the -secretase cleavage site (671M I) eliminated production of human A. High
levels of A1-42 resulted in age-dependent formation of
amyloid plaques in FAD-mutant hAPP mice but not in expression-matched wild-type hAPP mice. Yet, significant decreases in the density of
SYN-IR presynaptic terminals were found in both groups of mice. Across
mice from different transgenic lines, the density of SYN-IR presynaptic
terminals correlated inversely with A levels but not with hAPP
levels or plaque load. We conclude that A is synaptotoxic even in
the absence of plaques and that high levels of A1-42 are insufficient to induce plaque formation in mice expressing wild-type hAPP. Our results support the emerging view that
plaque-independent A toxicity plays an important role in the
development of synaptic deficits in AD and related conditions.
Key words:
Alzheimer's disease; amyloid; APP; neurodegeneration; synapses; transgenic mice
Copyright © 2000 Society for Neuroscience 0270-6474/00/20114050-09$05.00/0
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