Most Down's syndrome (DS) patients develop Alzheimer's disease (AD) neuropathology. Astrocyte and neuronal cultures derived from fetal DS brain show alterations in the processing of amyloid β precursor protein (AβPP), including increased levels of AβPP and C99, reduced levels of secreted AβPP (AβPPs) and C83, and intracellular accumulation of insoluble Aβ42. This pattern of AβPP processing is recapitulated in normal astrocytes by inhibition of mitochondrial metabolism, consistent with impaired mitochondrial function in DS astrocytes. Intracellular Aβ42 and reduced AβPPs are also detected in DS and AD brains. The survival of DS neurons is markedly increased by recombinant or astrocyte-produced AβPPs, suggesting that AβPPs may be a neuronal survival factor. Thus, mitochondrial dysfunction in DS may lead to intracellular deposition of Aβ42, reduced levels of AβPPs, and a chronic state of increased neuronal vulnerability.