Mitochondrial accumulation of APP and Abeta: significance for Alzheimer disease pathogenesis

Abstract

Accumulating evidence suggest that alterations in energy metabolism are among the earliest events that occur in the Alzheimer disease (AD) affected brain. Energy consumption is drastically decreased in the AD-affected regions of cerebral cortex and hippocampus pointing towards compromised mitochondrial function of neurons within specific brain regions. This is accompanied by an elevated production of reactive oxygen species contributing to increased rates of neuronal loss in the AD-affected brain regions. In this review, we will discuss the role of mitochondrial function and dysfunction in AD. We will focus on the consequences of amyloid precursor protein and amyloid-beta peptide accumulation in mitochondria and their involvement in AD pathogenesis.

Fig 1

APP is localized to mitochondria. APP N-terminal contains a mitochondrial targeting sequence (positively charged aa 40, 44 and 51) and is incompletely imported into mitochondria due to an acidic stop translocation sequence (aa 220–290). Subsequently APP may either be degraded by proteases such as Omi in the intermembrane space or form supercomplexes with the TOM and TIM complexes whereby blocking the import machinery.

Fig 2

Aβ_1–40 and Aβ_1–42 are taken up by mitochondria through the TOM machinery. After import most of the Aβ will reside in the inner mitochondrial membrane, where it possibly can inhibit the respiration chain (CI-V) resulting in an increased production of ROS. However, a fraction will also reach the matrix where it either can be degraded by proteases like PreP and IDE or interact with proteins such as CypD and ABAD.