Credit:  Busciglio et al., reprinted with permission from Neuron

A distinct feature of Down syndrome (DS), or trisomy 21, is the onset of Alzheimer disease (AD) by middle age. Previous studies have suggested that increased expression of the gene encoding the amyloid β precursor protein (Aβ-PP) may underlie the development of AD in DS. However, DS individuals also have mitochondrial defects, which have been associated with neurodegeneration in other disorders. In a recent report, Busciglio et al. (Neuron 33, 677–688; 2002) draw the link between Aβ-PP metabolism and mitochondrial dysfunction in DS.

Shown here are human astrocytes in cell culture stained with propidium iodide (red) and an antibody that recognizes Aβ-42 (green), a product of AβPP. Intracellular accumulation of Aβ-42 has been associated with AD in previous studies. The authors found that astrocytes treated with a mitochondrial inhibitor, m-chlorophynhydrazone (CCCP) also accumulated Aβ-42 (arrows; right). Untreated astrocytes did not accumulate Aβ-42 (left). The accumulation is similar to that seen in astrocytes derived from the brains of DS individuals, indicating that mitochondrial impairment may underlie the Aβ-42 defect in vivo.

Busciglio et al. went on to demonstrate that mitochondrial inhibition mimicked other alterations in Aβ-PP processing that occur in DS. Secreted AβPP, for example, was found to be reduced in both DS neurons and mitochondria-inhibited neurons. As secreted Aβ-PP promoted survival of DS neurons in vitro, its reduction could lead to neurodegeneration. The authors propose that impaired energy metabolism in DS neurons leads to alterations in the processing of Aβ-PP. Chronic Aβ-PP overexpression due to increased gene dosage could in turn impair mitochondrial function, they speculate, through direct toxicity or because of the metabolic costs of clearing aggregated proteins.