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Volume 16, Number 23,
Issue of December 1, 1996
pp. 7533-7539
Copyright ©1996 Society for Neuroscience
Amyloid  Peptide of Alzheimer's Disease Downregulates Bcl-2
and Upregulates Bax Expression in Human Neurons
Received July 30, 1996; revised Sept. 17, 1996; accepted Sept. 18, 1996.
Eric Paradis1,
Hélène Douillard1,
Maria Koutroumanis1,
Cynthia Goodyer2, and
Andréa LeBlanc1, 3
1 The Bloomfield Center for Research in Aging, Lady
Davis Institute for Medical Research, The Mortimer B. Davis Jewish
General Hospital, Montréal, Québec, Canada, and the
Departments of 2 Pediatrics and 3 Neurology and
Neurosurgery, McGill University, Montréal, Québec, Canada
Neuronal apoptosis is a suspected cause of neurodegeneration
in Alzheimer's disease (AD). Increased levels of amyloid  peptide (A) induce neuronal apoptosis in vitro and in
vivo. The underlying molecular mechanism of A neurotoxicity
is not clear. The normal concentration of A in cerebrospinal fluid
is 4 nM. We treated human neuron primary cultures with 100 nM amyloid peptides A1-40 and
A1-42 and the control reverse peptide
A40-1. We find that although little neuronal apoptosis
is induced by either peptide after 3 d of treatment,
A1-42 provokes a rapid and sustained downregulation of
a key anti-apoptotic protein, bcl-2, whereas it increases levels of
bax, a protein known to promote cell death. In contrast, the
A1-40 downregulation of bcl-2 is gradual, although the
levels are equivalent to those of A1-42-treated neurons
by 72 hr of treatment. A1-40 does not upregulate bax
levels. The control, reverse peptide A40-1, does not
affect either bcl-2 or bax protein levels. In addition, we found that
the A1-40- and A1-42- but not
A40-1-treated neurons had increased vulnerability to
low levels of oxidative stress. Therefore, we propose that although
high physiological amounts of A are not sufficient to induce
apoptosis, A depletes the neurons of one of its anti-apoptotic
mechanisms. We hypothesize that increased A in individuals renders
the neurons vulnerable to age-dependent stress and
neurodegeneration.
Key words:
amyloid peptide;
human neuron primary cultures;
bcl-2;
bax;
apoptosis;
Alzheimer's disease
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