AMYLOID-BETA PEPTIDE OF ALZHEIMERS-DISEASE DOWN-REGULATES BCL-2 AND UP-REGULATES BAX EXPRESSION IN HUMAN NEURONS

Neuronal apoptosis is a suspected cause of neurodegeneration in Alzhei mer's disease (AD). Increased levels of amyloid beta peptide (A beta) induce neuronal apoptosis in Vitro and in vivo. The underlying molecul ar mechanism of A beta neurotoxicity is not clear. The normal concentr ation of A beta in cerebrospinal fluid is 4 nM. We treated human neuro n primary cultures with 100 nM amyloid beta peptides A beta(1-40) and A beta(1-42) and the control reverse peptide A beta(40-1). We find tha t although little neuronal apoptosis is induced by either peptide afte r 3 d of treatment, A beta(1-42) provokes a rapid and sustained downre gulation of a key anti-apoptotic protein, bcl-2, whereas it increases levels of bar, a protein known to promote cell death. In contrast, the A beta(1-40) downregulation of bcl-2 is gradual, although the levels are equivalent to those of A beta(1-42)-treated neurons by 72 hr of tr eatment. A beta(1-40) does not upregulate bar levels. The control, rev erse peptide A beta(40-1), does not affect either bcl-2 or bar protein levels. In addition, we found that the A beta(1-40)- and A beta(1-42) - but not A beta(40-1)- treated neurons had increased vulnerability to low levels of oxidative stress. Therefore. we propose that although h igh physiological amounts of A beta are not sufficient to induce apopt osis, A beta depletes the neurons of one of its antiapoptotic mechanis ms. We hypothesize that increased A beta in individuals renders the ne urons vulnerable to age-dependent stress and neurodegeneration.