The Mitochondrial Peptidasome, PreP, relation to Alzheimer Disease

Abstract: Amyloid-? (A?) is the toxic peptide implicated in the pathogenesis of Alzheimer Disease (AD). Accumulation of A? has been shown in brain mitochondria from AD patients and AD mice models. The occurrence of A? in the mitochondrial matrix leads to free radical generation and apoptosis in neurons.In our studies, A? was found in brain mitochondria of living patients with plaque pathology. Extracellular A? was taken up by neuroblastoma cells and was found in the mitochondria. Moreover, we showed that A?40 and A?42 are transported into mitochondria via the Translocase of the Outer Membrane, the TOM machinery.We have identified the mitochondrial A?-degrading protease hPreP, in human brain mitochondrial matrix. PreP is a metalloprotease, originally identified as presequence protease, but was also shown to degrade other unstructured peptides including A?. Immunoinactivation of PreP in human brain mitochondria revealed PreP to be the protease responsible for A? degradation in mitochondria.Also, we have investigated if genetic variation in the gene encoding hPreP is associated with AD by genotyping 19 single nucleotide polymorphisms (SNPs) in the Swedish population. The study did not show a genetic association between any of the genotyped SNPs and the risk to AD. However, the biochemical analysis of four SNPs selected on the basis of their location within a structural homology model of hPreP revealed a decreased activity compared to wildtype.Interestingly, the activity of PreP in human brain mitochondrial matrix in AD individuals was significantly lower compared to non-dement aged-matched controls. These findings were also confirmed in brain mitochondrial matrix of AD mouse models. These results suggest that a decreased PreP activity may contribute to A? aggregation and accumulation inside mitochondria leading to neuronal death in AD. In summary, our findings show that the degradation of A? by hPreP may be of importance in the pathology of AD.