Evidence for apoptosis in the fetal Down syndrome brain

In Down syndrome, enhanced apoptosis (programmed cell death) may play a rol e in the pathogenesis of characteristic early mental retardation and precoc ious neurodegeneration of Alzheimer type. Various apoptosis-associated prot eins (Bax, Bcl-2, Fas, p53, Hsp70, neuronal apoptosis inhibitory protein-li ke immunoreactivity) were investigated in four different cortical regions a nd the cerebellum of one fetal Down syndrome (35 weeks' gestation) postmort em brain sample compared with a control brain sample. The most impressive f inding was an at least fivefold elevation of Bax protein together with decr eased Bcl-2 values in all Down syndrome cerebral regions investigated. In a ddition, antiapoptotic, presumably caspase-inhibitory, principles like heat shock protein 70 and neuronal apoptosis inhibitory protein were also reduc ed. Whereas Fas protein, an important member of receptor-mediated apoptosis , was inconsistently altered, a rather surprising finding was reduced proap optotic, regulatory protein p53 in four of five regions. The findings are i n good agreement with the proposed role of the Bcl-2 protein family in regu lating developmental (naturally occurring) apoptotic neuronal death arid fu rther suggest that developmental apoptosis may be inappropriately commandee red by so far undefined pathologic processes in Down syndrome.