Close encounter: mitochondria, endoplasmic reticulum and Alzheimer's disease

Abstract

EMBO J (2012) 31 21, 4106–4123. doi:; DOI: 10.1038/emboj.2012.202; published online August 14 2012

Alzheimer’s disease (AD) is characterized by the loss of hippocampal and cortical neurons as a consequence of the accumulation of amyloid-β (Aβ). Aβ is produced from the amyloid precursor protein (APP) by the γ-secretase complex components presenilin-1 (PS1) and -2 (PS2), which are mutated in genetic forms of AD. In this issue, Schon and coworkers show that PS1 and PS2 are located at the interface between mitochondria and endoplasmic reticulum (ER). In models of familial and sporadic AD, these two organelles are juxtaposed closely, affecting shared lipid metabolic pathways. The interface between mitochondria and ER emerges as a new potential determinant of AD pathogenesis.

Figure 1

Schematic representation of the changes in the ER–mitochondria interface in models of AD. Left: the normal ER–mitochondria interface; the known molecular tethers and PS1 and PS2 are shown. Right: the closer juxtaposition observed in models of AD, where PS is lacking. Note that the MAM has increased in size. Mfn, mitofusin; Drp1, dynamin-related protein 1; IP3R, inositol triphosphate receptor; VDAC, voltage-dependent anion channel; GRP75, heat-shock protein 75; PS, presenilin; the orange region on the ER illustrates the MAM.