Mutations in nuclear-encoded mitochondrial genes are responsible for a broad spectrum of disorders among which Leigh syndrome is the most common in infancy. No effective therapies are available for this severe disease mainly because of the limited capabilities of the standard adeno-associated viral (AAV) vectors to transduce both peripheral organs and the CNS when injected systemically in adults. Here, we used the brain-penetrating AAV-PHP.B vector to reinstate gene expression in the Ndufs4 knockout mouse model of Leigh syndrome. Intravenous delivery of an AAV.PHP.B-Ndufs4 vector in 1-month-old knockout mice restored mitochondrial complex I activity in several organs including the CNS. This gene replacement strategy extended lifespan, rescued metabolic parameters, provided behavioural improvement, and corrected the pathological phenotype in the brain, retina, and heart of Ndufs4 knockout mice. These results provide a robust proof that gene therapy strategies targeting multiple organs can rescue fatal neurometabolic disorders with CNS involvement.

Alterations of excitatory synaptic function are the strongest correlate to the pathologic disturbance of cognitive ability observed in the early stages of Alzheimer's disease (AD). This pathologic feature is driven by amyloid-b oligomers (Abos) and propagates from neuron to neuron. Here, we investigated the mechanism by which Abos affect the function of synapses and how these alterations propagate to surrounding healthy neurons. We used complementary techniques ranging from electrophysiological recordings and molecular biology to confocal microscopy in primary cortical cultures, and from acute hippocampal and cortical slices from male wild-type and amyloid precursor protein (APP) knock-out (KO) mice to assess the effects of Abos on glutamatergic transmission, synaptic plasticity, and dendritic spine structure. We showed that extracellular application of Abos reduced glutamatergic synaptic transmission and long-term potentiation. These alterations were not observed in APP KO neurons, suggesting that APP expression is required. We demonstrated that Abos/APP interaction increases the amyloidogenic processing of APP leading to intracellular accumulation of newly produced Abos. Intracellular Abos participate in synaptic dysfunctions as shown by pharmacological inhibition of APP processing or by intraneuronal infusion of an antibody raised against Abos. Furthermore, we provide evidence that following APP processing, extracellular release of Abos mediates the propagation of the synaptic pathology characterized by a decreased spine density of neighboring healthy neurons in an APP-dependent manner. Together, our data unveil a complementary role for Abos in AD, while intracellular Abos alter synaptic function, extracellular Abos promote a vicious cycle that propagates synaptic pathology from diseased to healthy neurons.