Altered neuronal endoplasmic reticulum-mitochondria coupling in a transgenic rat model of Alzheimer?s disease

MARTINO ADAMI PV; BARRANTES, FJ; ROTONDARO, MC; CASTAÑO E.M; HAJNÓCZKY, G.; MORELLI, L.

Congreso; 26th Biennial Meeting of the International Society for Neurochemistry (ISN).; 2017

Neuronal bioenergetic failure has been suggested as an early event leading to cognitive impairment and ultimately to Alzheimer?s disease (AD), a neurodegenerative disorder characterized by intraneuronal amyloid b (iAb) accumulation. Several metabolic neuronalfunctions are regulated by close physical communications that mitochondria make with the endoplasmic reticulum (ER), involving distances of approximately 10?30 nm. In this context, it is relevant to evaluate the impact of iAb on such distances by an accuratemethod. To address this question, we employed hippocampal primary neurons from embryonic transgenic McGill-R-Thy1-APP rats, which mimic AD, and wild-type (control) animals. Neurons were transfected with plasmids coding drug-inducible synthetic interorganellar linkers targeting outer mitochondrial membrane or ER fused to fluorescent proteins that form a FRET pair upon addition of rapamycin. Live imaging data recorded by multi-colour epifluorescence microcospy revealed that ER-mitochondria distance is altered in transgenic neurons as early as 7 days in vitro as compared to controls. Complementary studies showed iAb accumulation and bioenergetic impairment, assessed by super-resolution microscopy and high-resolution respirometry, respectively. These results may suggest that iAb accumulation disrupts ER-mitochondria coupling which in turn alters proper mitochondrial function. Understanding the mechanisms that lead to neuronal bioenergetic failure may be useful to develop new specific therapeutic strategies.