Amyloid beta overproduction and alterations in the communication between organelles: possible mechanisms linked with neurodegeneration

ROTONDARO, CECILIA; HAJNÓCZKY, GYÖRGY; MARTINO ADAMI, PAMELA V.; CUELLO, A. CLAUDIO; CASTAÑO, EDUARDO M.; MORELLI, LAURA

CABA

Congreso; XX Congreso Argentino de la Enfermedad de Alzheimer y otros trastornos cognitivos; 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 β (iAβ) accumulation. Several metabolic neuronal functions 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 iAβ on such distances by an accurate method. 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 iAβ accumulation and bioenergetic impairment, assessed by super-resolution microscopy and high-resolution respirometry, respectively. These results may suggest that iAβ 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.