Y. Goodman et Mp. Mattson, SECRETED FORMS OF BETA-AMYLOID PRECURSOR PROTEIN PROTECT HIPPOCAMPAL-NEURONS AGAINST AMYLOID BETA-PEPTIDE-INDUCED OXIDATIVE INJURY, Experimental neurology, 128(1), 1994, pp. 1-12
Alternative processing of the beta-amyloid precursor protein (beta APP
) can result in liberation of either secreted forms of beta APP (APP(s
)s), which may play roles in neuronal plasticity and survival, or amyl
oid beta-peptide (A beta p), which can be neurotoxic. In rat hippocamp
al cell cultures A beta 1-40 caused a time- and concentration-dependen
t reduction in neuronal survival. APP(s)695 and APP(s)751 significantl
y reduced A beta-induced injury in a concentration-dependent manner. A
beta B caused an elevation of intracellular calcium levels ([Ca2+](i)
) which was significantly attenuated by APP(s)s. A beta also caused in
duction of reactive oxygen species (measured using the oxidation-sensi
tive fluorescent dye 2,7-dichlorofluorescin) which was also attenuated
by APP(s)s, A beta-induced neurotoxicity and elevations of [Ca2+](i)
were attenuated by vitamin E, suggesting the involvement of free radic
als in A beta-induced loss of calcium homeostasis and neuronal injury.
The APP(s)s protected neurons against oxidative injury caused by expo
sure to iron. Taken together, the data indicate that A beta kills neur
ons by causing free radical production and increased [Ca2+](i.) APP(s)
s can protect neurons against such free radical- and Ca2+-mediated inj
ury. These findings support the hypothesis that altered processing of
beta APP contributes to neuronal injury in Alzheimer's disease. (C) 19
94 Academic Press, Inc.