Can ER-Mitochondria coupling, bioenergetics and accumulation of Aβ be linked together in a common and early pathogenic pathway in Alzheimer ?

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

Simposio; Alexander von Humboldt Kolleg Current Advances on Neurodegeneration: from Molecular Biology to Translational Medicine; 2017

Alexander von Humboldt -UNC

Bioenergetic function is mainly regulated bycommunications that mitochondria (Mito) make with a specialized region of theendoplasmic reticulum (ER). Juxtaposition is mediated by protein structures,covering 5-20% of Mito surface and spanning 5?20 nm when connecting to smoothER. Neuronalbioenergetic dysfunction has been suggested as an early event and as a causefor synaptic deficiency and cognitive impairment in Alzheimer?s disease (AD).However, the molecular mechanisms underlying this event are poorlycharacterized. We recently showed in an animal model of early AD , the transgenicMcGill-R-Thy1-APP rats (Tg) that hippocampal synaptosomes of 6 month-oldanimals have a lower capacity to provide ATP when an extra energy demand isrequired. This metabolic dysfunction is associated with cognitive impairmentand may be partially explained by diminished Complex-I enzymatic activity. Experimentalevidence using synthetic Aβ peptidesand cell lines showed increased ER-Mito coupling suggesting that Aβ accumulation upregulates ER-Mito contacts,leading to mitochondrial dysfunction possibly through Ca2+overloading. To address the impact of intracellular Aβ (iAβ) accumulation in ER-Mitocoupling we employed hippocampal primary neurons from embryonic Tg rats and wild-typeanimals. Neurons were transfected with plasmids coding drug-inducible syntheticinter-organellar short (~5 nm) or long (~20 nm) linkers targeting outer Mito membrane and ER, fused tofluorescent proteins (CFP or YFP) that form aFRET pair upon addition of rapamycin. Live imaging data recorded by multi-colourepifluorescence microcospy revealed that neurons from Tg rats display ?relaxed?short ER-Mito distances and no changes were observed using long linkers. Thesealterations correlate with bioenergetic impairment and iAβlevels assessed by high-resolutionrespirometry and ELISA Multiplex, respectively. ER-Mito distance can varydepending on the metabolic needs of the cell and the presence of stressors. Tighterassociations (~10 nm) are likely to better support lipid transfer while someseparation (~20 nm) is needed for Ca2+ delivery. Our results suggestthat iAβ accumulation downregulates ER-Mito coupling altering lipids ratherthan Ca2+ transport. The present study provides insights into theearliest molecular mechanisms and biochemical events that may happen in neuronsform AD brain, connecting ER-Mito coupling with specific lipid changes and synapticbioenergetic deficit