Amyloid-β Peptides are Generated in Mitochondria-Associated Endoplasmic Reticulum Membranes

Abstract

Extracellular aggregates of amyloid-β peptides (Aβ) are a hallmark in Alzheimer's disease (AD) brains. Recent findings suggest that Aβ is generated intracellularly and potential production sites include endosomes and trans-Golgi network. We determined the production of Aβ in subcellular fractions isolated from mouse brain. We found that a considerable amount of Aβ is produced at mitochondria-endoplasmic reticulum (ER) contact sites including outer mitochondrial membrane and mitochondria-associated ER membranes. Enhanced Aβ production at this site may disturb ER, mitochondrial and mitochondria-ER contact site function. This may be one key step in the cascade of events eventually leading to neurodegeneration in AD.

Increased localization of APP‐C99 in mitochondria‐associated ER membranes causes mitochondrial dysfunction in Alzheimer disease

“…In addition to those sites, C99 (in red) also colocalized with regions where both ER (in green) and mitochondria (in blue) were present (white arrows in Fig 2E and Appendix Fig S2D). This suggests that, like presenilins (Area‐Gomez et al , 2009), C99 can be localized to areas of the ER apposed to mitochondria, that is, MAM, and is consistent with the fact that γ‐secretase activity is present in this compartment (Area‐Gomez et al , 2009; Schreiner et al , 2015). …”

“…Consistent with the data of others (Das et al , 2016), FL‐APP and BACE1 co‐migrated partially with a marker for endosomes (Rab7), but not with lysosomal, ER‐intermediate, or MAM markers (Fig 2C). Similarly, the APP‐CTFs C83 and C99 co‐migrated with endosomal and lysosomal markers (Rab5, Rab7, and LAMP‐2) (Haass et al , 2012; Das et al , 2016), whereas PS1 co‐migrated with MAM markers, such as FACL4 (Area‐Gomez et al , 2009; Newman et al , 2014; Schreiner et al , 2015). We reasoned that the difficulty in seeing APP‐CTFs and PS1 together was probably due to the rapid cleavage of the CTFs by γ‐secretase once both are in the same compartment.…”

“…We and others have shown that presenilins and γ‐secretase activity localize to MAM (Area‐Gomez et al , 2009; Newman et al , 2014; Schreiner et al , 2015). Moreover, MAM functionality (Area‐Gomez et al , 2012) and ER–mitochondrial apposition (Area‐Gomez et al , 2012; Hedskog et al , 2013) are increased in AD.…”

“…We propose that, while the majority of C99 resides in endosomes, C99 can traffic to MAM regions in the ER, where it is cleaved rapidly by γ‐secretase to produce Aβ and AICD (Area‐Gomez et al , 2009; Schreiner et al , 2015). We note that although the mechanism by which C99 translocates to ER‐MAM is unknown, recent work has demonstrated the existence of ER‐endosome contacts (Rowland et al , 2014) where lipid and protein exchange may occur (Wilhelm et al , 2017).…”

The coming of age of the mitochondria–ER contact: a matter of thickness

“…Recent studies from Area-Gomez et al 30,57 have shown that the lipid-related function of the MAMs is increased in cells expressing mutated forms of familial AD proteins Presenilin-1 and Presenilin-2; also, that the presenilins and their gammasecretase activity are enriched at the MAM, where the Aβ peptide is indeed also generated. 58 Fibroblasts from AD patients, whose symptoms include aberrant lipid metabolism, 59 have more 'long' (50-200 nm) and 'very long' (4200 nm) MERCs, and increased lipid biosynthesis/transfer. These observations led to the formulation of the 'MAM hypothesis', which states that AD is essentially a disorder of ER-mitochondrial communication.…”