Relaxed mitochondria-endoplasmic reticulum connections and amyloid β accumulation: a common neurotoxic pathway?

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

Congreso; Reunion de Sociedades Conjuntas; 2017

Alzheimer?s disease (AD) is a neurodegenerative and progressive disorder with no effective treatment to prevent or delay the onset of the disease. Intraneuronal amyloid β (iAβ) accumulation and bioenergetic failure have been suggested as early events in the progression of AD. Bioenergetic function is mainly regulated by communications that mitochondria make with a specialized region of the endoplasmic reticulum (ER), called mitochondria-ER connections (MERC), which involve variable distances of 5-30 nm.To evaluate MERC in an early AD model, we employed hippocampal primary neurons from transgenic (Tg) McGill-R-Thy1-APP and wild-type (control) rats. Neurons from Tg rats with 7 days in vitro (DIV7) display a diffuse pattern of iAβ accumulation associated withthe outer mitochondrial membrane (OMM), secrete low levels of Aβ to the conditioned medium and, despite not showing mitochondrial ultrastructural alterations, exhibit lower capacity to provide ATP in situations where the energy demand increases. Cultures were transfected with plasmids coding drug-inducible synthetic interorganellar linkers targeting OMM or ER fused to fluorescent proteins that form a FRET pair upon addition of rapamycin. Live imaging data recorded by multi-colour epifluorescence microscopy revealed that neurons DIV7 from Tg rats display relaxed ER-mitochondria connectionswhen involving distances of less than 10 nm as compared to control neurons. Given that these short distances might favour lipid transfer between ER and mitochondria, we assessed the levels of cardiolipin, a mitochondrial phospholipid which possess an important rolein the assembly of the inner mitochondrial membrane. Preliminary results show that levels of cardiolipin are decreased in Tg neurons with no differences in mitochondrial number. Together these results suggest that the mechanisms by which iAβ accumulation impairsbioenergetics may be mediated by alterations in MERC that cause diminished lipid transport.