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

CASTAÑO E.M; MORELLI L; MARTINO ADAMI PV; CUELLO, C; HAJNÓCZKY, G.

Conferencia; Conference; 2017

Alzheimer?s disease (AD) is aneurodegenerative and progressive disorder with no effective treatment toprevent or delay the onset of the disease. Intraneuronal amyloid β (iAβ)accumulation and bioenergetic failure have been suggested as early events in theprogression of AD. Bioenergetic function is mainly regulated by communicationsthat mitochondria make with a specialized region of the endoplasmic reticulum(ER), called mitochondria-ER connections (MERC), which involve variabledistances of 5-30 nm.To evaluate MERC in an early AD model, we employed hippocampal primary neuronsfrom transgenic (Tg) McGill-R-Thy1-APP and wild-type (control) rats. Neuronsfrom Tg rats with 7 days in vitro (DIV7) display a diffuse pattern of iAβaccumulation associated withthe outer mitochondrial membrane (OMM), secrete low levels of Aβ to theconditioned medium and, despite not showing mitochondrial ultrastructuralalterations, exhibit lower capacity to provide ATP in situations where theenergy demand increases. Cultures were transfected with plasmids codingdrug-inducible synthetic interorganellar linkers targeting OMM or ER fused tofluorescent proteins that form a FRET pair upon addition of rapamycin. Liveimaging data recorded by multi-colour epifluorescence microscopy revealed thatneurons 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 andmitochondria, we assessed the levels of cardiolipin, a mitochondrialphospholipid which possess an important rolein the assembly of the inner mitochondrial membrane. Preliminary results showthat levels of cardiolipin are decreased in Tg neurons with no differences inmitochondrial number. Together these results suggest that the mechanisms bywhich iAβ accumulation impairsbioenergetics may be mediated by alterations in MERC that cause diminishedlipid transport.