THE EFFECT OF AMYLOID β-PEPTIDE ON ER-MITOCHONDRIA CONTACT IN ALZHEIMER’S DISEASE

Abstract

Cellular organelles are in close proximity at specialized contact sites where important cellular processes take place. For example, Ca2+-homeostasis, lipid synthesis, apoptosis and autophagy are regulated at the ER-mitochondria axis and interestingly all these processes are altered in Alzheimer's disease (AD). We have previously shown that modulation of ER-mitochondria contacts affect the assembly and maturation of the γ-secretase complex as well as generation of amyloid β-peptide (Aβ) (Leal et al 2016). Here we have investigated the effect of Aβ on the structure and dynamics of ER-mitochondria contacts in human tissue and AD mouse models. Human brain biopsies were collected from patients undergoing neurosurgery due to idiopathic normal pressure hydrocephalus (iNPH). The biopsies were stained for amyloid plaques (Aβ) and neurofibriallary tangles (tau). Mouse brain tissue was obtained from wt and tgAPPswe/lon mice of different ages. ER-mitochondria contact length and number were analyzed by structural electron microscopy. In addition, ER-mitochondria contact is being currently analyzed by proximity ligation assay (PLA) in primary neurons derived from a novel APP-knockin mouse model, APPNL-F. From brain biopsies we were able to characterise the structure of ER-mitochondria contacts in human brain. EM analysis of mouse brain material shows that ER-mitochondria apposition is affected by Aβ accumulation. Increased length of ER-mitochondria contacts were detected in tgAPPswe/lon mice at 6 months of age. Using PLA we can also visualize and quantify contact sites in APPNL-F mice. On-going analysis will reveal if Aβ accumulation affects ER-mitochondria apposition at an early stage before plaque pathology. The mechanisms underlying synapse loss and neurodegeneration in AD are not yet clarified. Here we show a close relationship between Aβ accumulation and regulation of ER-mitochondria contact and discuss its role in AD pathogenesis.