5 years ago

Mitochondria-associated ER membranes and Alzheimer disease

The series of events underlying the pathogenesis of Alzheimer disease (AD) in unknown. The most widely accepted hypothesis is called the amyloid cascade, based on the observation that the brains of AD patients contain high levels of extracellular plaques, composed mainly of β-amyloid (Aβ), and intracellular tangles, composed of hyperphosphorylated forms of the microtubule-associated protein tau. However, AD is also characterized by other features, including aberrant cholesterol, phospholipid, and calcium metabolism, and mitochondrial dysfunction, all ostensibly unrelated to plaque and tangle formation. Notably, these ‘other’ aspects of AD pathology are functions related to mitochondria-associated ER membranes (MAM), a subdomain of the endoplasmic reticulum (ER) that is apposed to, and communicates with, mitochondria. Given the potential relationship between MAM and AD, we explored the possibility that perturbed MAM function might play a role in AD pathogenesis. We found that γ-secretase activity, which processes the amyloid precursor protein to generate Aβ, is located predominantly in the MAM, and that ER–mitochondrial apposition and MAM function are increased significantly in cells from AD patients. These observations may help explain not only the aberrant Aβ production, but also many of the ‘other’ biochemical and morphological features of the disease. Based on these, and other, data we propose that AD is fundamentally a disorder of ER–mitochondrial hyperconnectivity.

Publisher URL: www.sciencedirect.com/science

DOI: S0959437X16300296

You might also like
Discover & Discuss Important Research

Keeping up-to-date with research can feel impossible, with papers being published faster than you'll ever be able to read them. That's where Researcher comes in: we're simplifying discovery and making important discussions happen. With over 19,000 sources, including peer-reviewed journals, preprints, blogs, universities, podcasts and Live events across 10 research areas, you'll never miss what's important to you. It's like social media, but better. Oh, and we should mention - it's free.

  • Download from Google Play
  • Download from App Store
  • Download from AppInChina

Researcher displays publicly available abstracts and doesn’t host any full article content. If the content is open access, we will direct clicks from the abstracts to the publisher website and display the PDF copy on our platform. Clicks to view the full text will be directed to the publisher website, where only users with subscriptions or access through their institution are able to view the full article.