The Blood-Brain Barrier Is Unaffected in the Ndufs4-/- Mouse Model of Leigh Syndrome.

Mitochondrial dysfunction plays a major role in physiological aging and in many pathological conditions. Yet, no study has explored the consequence of primary mitochondrial deficiency on the blood-brain barrier (BBB) structure and function. Addressing this question has major implications for pharmacological and genetic strategies aimed at ameliorating the neurological symptoms that are often predominant in patients suffering from these conditions. In this study, we examined the permeability of the BBB in the Ndufs4-/- mouse model of Leigh syndrome (LS). Our results indicated that the structural and functional integrity of the BBB was preserved in this severe model of mitochondrial disease. Our findings suggests that pharmacological or gene therapy strategies targeting the central nervous system in this mouse model and possibly other models of mitochondrial dysfunction require the use of specific tools to bypass the BBB. In addition, they raise the need for testing the integrity of the BBB in complementary in vivo models.

Gene replacement therapy provides benefit in an adult mouse model of Leigh syndrome.

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.

Effect of Aß Oligomers on Neuronal APP Triggers a Vicious Cycle Leading to the Propagation of Synaptic Plasticity Alterations to Healthy Neurons.

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-ß oligomers (Aßos) and propagates from neuron to neuron. Here, we investigated the mechanism by which Aßos 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 Aßos on glutamatergic transmission, synaptic plasticity, and dendritic spine structure. We showed that extracellular application of Aßos 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 Aßos/APP interaction increases the amyloidogenic processing of APP leading to intracellular accumulation of newly produced Aßos. Intracellular Aßos participate in synaptic dysfunctions as shown by pharmacological inhibition of APP processing or by intraneuronal infusion of an antibody raised against Aßos. Furthermore, we provide evidence that following APP processing, extracellular release of Aßos 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 Aßos in AD, while intracellular Aßos alter synaptic function, extracellular Aßos promote a vicious cycle that propagates synaptic pathology from diseased to healthy neurons.SIGNIFICANCE STATEMENT Here we provide the proof that a vicious cycle between extracellular and intracellular pools of Aß oligomers (Aßos) is required for the spreading of Alzheimer's disease (AD) pathology. We showed that extracellular Aßos propagate excitatory synaptic alterations by promoting amyloid precursor protein (APP) processing. Our results also suggest that subsequent to APP cleavage two pools of Aßos are produced. One pool accumulates inside the cytosol, inducing the loss of synaptic plasticity potential. The other pool is released into the extracellular space and contributes to the propagation of the pathology from diseased to healthy neurons. Pharmacological strategies targeting the proteolytic cleavage of APP disrupt the relationship between extracellular and intracellular Aß, providing a therapeutic approach for the disease.