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The Journal of Neuroscience, October 15, 1998, 18(20):8311-8321
Protease Inhibitor Coinfusion with Amyloid  -Protein Results in
Enhanced Deposition and Toxicity in Rat Brain
Sally A.
Frautschy1, 2, 3,
David L.
Horn2,
Jason J.
Sigel2,
Marni E.
Harris-White2,
John J.
Mendoza2,
Fusheng
Yang2,
T. C.
Saido4, and
Gregory M.
Cole1, 2, 3
1 Geriatric Research Education and Clinical Center,
Sepulveda Veterans Affairs Medical Center, Sepulveda, California 91343, Departments of 2 Medicine and 3 Neurology,
University of California, Los Angeles, Los Angeles, California 90095, and 4 Laboratory for Proteolytic Neuroscience, The
Institute of Physical and Chemical Research, Brain Science Institute,
Saitama 338-8570, Japan
Amyloid  -protein, A, is normally produced in brain and is
cleared by unknown mechanisms. In Alzheimer's disease (AD), A accumulates in plaque-like deposits and is implicated
genetically in neurodegeneration. Here we investigate mechanisms
for A degradation and A toxicity in vivo, focusing
on the effects of A40, which is the peptide that accumulates in
apolipoprotein E4-associated AD. Chronic intraventricular infusion of
A40 into rat brain resulted in limited deposition and toxicity.
Coinfusion of A40 with the cysteine protease inhibitor leupeptin
resulted in increased extracellular and intracellular A
immunoreactivity. Analysis of gliosis and TUNEL in neuron layers of the
frontal and entorhinal cortex suggested that leupeptin exacerbated
A40 toxicity. This was supported further by the neuronal staining of
cathepsin B in endosomes or lysosomes, colocalizing with intracellular
A immunoreactivity in pyknotic cells. Leupeptin plus A40 caused
limited but significant neuronal phospho-tau immunostaining in the
entorhinal cortex. Intriguingly, A40 plus leupeptin induced
intracellular accumulation of the more toxic A, A42, in a small
group of septal neurons. Leupeptin infusion previously has been
reported to interfere with lysosomal proteolysis and to result in the
accumulation of lipofuscin, dystrophic neurites, tau- and
ubiquitin-positive inclusions, and structures resembling paired helical
filaments. Coinfusion of A40 with the serine protease inhibitor
aprotinin also increased diffuse extracellular deposition but reduced
astrocytosis and TUNEL and was not associated with intracellular A
staining. Collectively, these data suggest that an age or
Alzheimer's-related defect in lysosomal/endosomal function could
promote A deposition and DNA fragmentation in neurons and glia
similar to that found in Alzheimer's disease.
Key words:
Alzheimer's disease; A; lysosome; cathepsins; leupeptin; aprotinin; neurotoxicity; in vivo; rat
Copyright © 1998 Society for Neuroscience 0270-6474/98/18208311-11$05.00/0
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