Cyclosporine A (CsA) prevents synaptic impairment caused by truncated tau by caspase-3.

During Alzheimer's (AD), tau protein suffers from abnormal post-translational modifications, including cleaving by caspase-3. These tau forms affect synaptic plasticity contributing to the cognitive decline observed in the early stages of AD. In addition, caspase-3 cleaved tau (TauC3) impairs mitochondrial dynamics and organelles transport, which are both relevant processes for synapse. We recently showed that the absence of tau expression reverts age-associated cognitive and mitochondrial failure by blocking the mitochondrial permeability transition pore (mPTP). mPTP is a mitochondrial complex involved in calcium regulation and apoptosis. Therefore, we studied the effects of TauC3 against the dendritic spine and synaptic vesicle formation and the possible role of mPTP in these alterations. We used mature hippocampal mice neurons to express a reporter protein (GFP, mCherry), coupled to full-length human tau protein (GFP-T4, mCherry-T4), and coupled to human tau protein cleaved at D421 by caspase-3 (GFP-T4C3, mCherry-T4C3) and synaptic elements were evaluated. Treatment with cyclosporine A (CsA), an immunosuppressive drug with inhibitory activity on mPTP, prevented ROS increase and mitochondrial depolarization induced by TauC3 in hippocampal neurons. These results were corroborated with immortalized cortical neurons in which ROS increase and ATP loss induced by this tau form were prevented by CsA. Interestingly, TauC3 expression significantly reduced dendritic spine density (filopodia type) and synaptic vesicle number in hippocampal neurons. Also, neurons transfected with TauC3 showed a significant accumulation of synaptophysin protein in their soma. More importantly, all these synaptic alterations were prevented by CsA, suggesting an mPTP role in these negative changes derived from TauC3 expression.

The Role of Mitochondrial Impairment in Alzheimer´s Disease Neurodegeneration: The Tau Connection.

Accumulative evidence has shown that mitochondrial dysfunction plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). Mitochondrial impairment actively contributes to the synaptic and cognitive failure that characterizes AD. The presence of soluble pathological forms of tau like hyperphosphorylated at Ser396 and Ser404 and cleaved at Asp421 by caspase 3, negatively impacts mitochondrial bioenergetics, transport, and morphology in neurons. These adverse effects against mitochondria health will contribute to the synaptic impairment and cognitive decline in AD. Current studies suggest that mitochondrial failure induced by pathological tau forms is likely the result of the opening of the mitochondrial permeability transition pore (mPTP). mPTP is a mitochondrial mega-channel that is activated by increases in calcium and is associated with mitochondrial stress and apoptosis. This structure is composed of different proteins, where Ciclophilin D (CypD) is considered to be the primary mediator of mPTP activation. Also, new studies suggest that mPTP contributes to Aß pathology and oxidative stress in AD. Further, inhibition of mPTP through the reduction of CypD expression prevents cognitive and synaptic impairment in AD mouse models. More importantly, tau protein contributes to the physiological regulation of mitochondria through the opening/interaction with mPTP in hippocampal neurons. Therefore, in this paper, we will discuss evidence that suggests an important role of pathological forms of tau against mitochondrial health. Also, we will discuss the possible role of mPTP in the mitochondrial impairment produced by the presence of tau pathology and its impact on synaptic function present in AD.

Truncated Tau Induces Mitochondrial Transport Failure Through the Impairment of TRAK2 Protein and Bioenergetics Decline in Neuronal Cells.

Mitochondria are highly specialized organelles essential for the synapse, and their impairment contributes to the neurodegeneration in Alzheimer's disease (AD). Previously, we studied the role of caspase-3-cleaved tau in mitochondrial dysfunction in AD. In neurons, the presence of this AD-relevant tau form induced mitochondrial fragmentation with a concomitant reduction in the expression of Opa1, a mitochondrial fission regulator. More importantly, we showed that caspase-cleaved tau affects mitochondrial transport, decreasing the number of moving mitochondria in the neuronal processes without affecting their velocity rate. However, the molecular mechanisms involved in these events are unknown. We studied the possible role of motor proteins (kinesin 1 and dynein) and mitochondrial protein adaptors (RhoT1/T2, syntaphilin, and TRAK2) in the mitochondrial transport failure induced by caspase-cleaved tau. We expressed green fluorescent protein (GFP), GFP-full-length, and GPF-caspase-3-cleaved tau proteins in rat hippocampal neurons and immortalized cortical neurons (CN 1.4) and analyzed the expression and localization of these proteins involved in mitochondrial transport regulation. We observed that hippocampal neurons expressing caspase-cleaved tau showed a significant accumulation of a mitochondrial population in the soma. These changes were accompanied by evident mitochondrial bioenergetic deficits, including depolarization, oxidative stress, and a significant reduction in ATP production. More critically, caspase-cleaved tau significantly decreased the expression of TRAK2 in immortalized and primary hippocampal neurons without affecting RhoT1/T2 and syntaphilin levels. Also, when we analyzed the expression of motor proteins-Kinesin 1 (KIF5) and Dynein-we did not detect changes in their expression, localization, and binding to the mitochondria. Interestingly, the expression of truncated tau significantly increases the association of TRAK2 with mitochondria compared with neuronal cells expressing full-length tau. Altogether these results indicate that caspase-cleaved tau may affect mitochondrial transport through the increase of TRAK2-mitochondria binding and reduction of ATP production available for the process of movement of these organelles. These observations are novel and represent a set of exciting findings whereby tau pathology could affect mitochondrial distribution in neurons, an event that may contribute to synaptic failure observed in AD.

Activation of the Melanocortin-4 Receptor Prevents Oxidative Damage and Mitochondrial Dysfunction in Cultured Hippocampal Neurons Exposed to Ethanol.

Excessive alcohol intake affects hippocampal function and neuronal communication through oxidative stress and mitochondrial impairment. Previous studies have suggested that the melanocortin system (MCS) plays an essential role in alcohol consumption and addiction. The MCS is a hypothalamic region involved in regulating inflammatory processes in the brain, and its pharmacological activation through the melanocortin-4 receptor (MC4R) reduces both alcohol consumption and the neuroinflammatory responses in the brain. However, the cellular mechanisms involved in the beneficial actions of MCS against ethanol toxicity are not entirely understood. The objective of this study was to investigate the protective role of the MC4R pharmacological activator RO27-3225 on oxidative damage and mitochondrial impairment present in hippocampal neuronal cultures acutely exposed to ethanol (50, 75 mM, 24 h). Pre-treatment with RO27-3225 (250 nM, 1 h) prevented reactive oxygen species (ROS) increase, dysregulation of cytosolic calcium homeostasis, and mitochondrial potential loss induced by ethanol. Improvement of mitochondrial failure produced by RO27-3225 was accompanied by a significant increase in ATP production in ethanol-treated neurons. More importantly, RO27-3225 promoted the activation of the antioxidant pathway Nrf-2, demonstrated by an increase in the expression and nuclear translocation of Nrf-2, and upregulation of mRNA levels of NAD(P)H quinone oxidoreductase 1 (NQO1), an antioxidant enzyme which expression is activated by this pathway. These results suggest that the stimulation of MC4R prevents oxidative damage and mitochondrial stress induced by ethanol through the activation of the Nrf-2 pathway in cultured hippocampal neurons. These results are novel and demonstrate the critical function of MC4R in promoting antioxidant defense and reducing mitochondrial damage produced by ethanol in the brain.

NADPH oxidase contributes to oxidative damage and mitochondrial impairment induced by acute ethanol treatment in rat hippocampal neurons.

Acute ethanol treatment induces neurodegeneration in cultured neurons and can lead to brain damage in animal models. Neuronal cells exposed to ethanol showed an increase in reactive oxygen species (ROS), oxidative damage and mitochondrial impairment contributing to synaptic failure. However, the underlying mechanisms of these events are not well understood. Here, we studied the contribution of NADPH oxidase, as a relevant source of ROS production in the brain, to mitochondrial impairment and oxidative stress induced by ethanol. We used primary hippocampal neurons subjected to an acute treatment of ethanol at increasing concentrations (25, 50, and 75 mM, 24 h), and we evaluated ROS production, mitochondrial function, and synaptic vesicle activity. Our studies showed that after ethanol administration, hippocampal neurons presented an increase in ROS levels, mitochondrial dysfunction, calcium handling defects, and synaptic impairment. Interestingly, treatment with the NADPH inhibitor, apocynin, significantly prevented oxidative stress, mitochondrial dysfunction, and the impairment of synaptic vesicle activity induced by ethanol treatment. These results indicate that NADPH oxidase could be a key participant in the molecular mechanism by which alcohol affects the brain.

Structural and Functional Abnormalities in the Olfactory System of Fragile X Syndrome Models.

Fragile X Syndrome (FXS) is the most common inherited form of intellectual disability. It is produced by mutation of the Fmr1 gene that encodes for the Fragile Mental Retardation Protein (FMRP), an important RNA-binding protein that regulates the expression of multiple proteins located in neuronal synapses. Individuals with FXS exhibit abnormal sensory information processing frequently leading to hypersensitivity across sensory modalities and consequently a wide array of behavioral symptoms. Insects and mammals engage primarily their sense of smell to create proper representations of the external world and guide adequate decision-making processes. This feature in combination with the exquisitely organized neuronal circuits found throughout the olfactory system (OS) and the wide expression of FMRP in brain regions that process olfactory information makes it an ideal model to study sensory alterations in FXS models. In the last decade several groups have taken advantage of these features and have used the OS of fruit fly and rodents to understand neuronal alteration giving rise to sensory perception issues. In this review article, we will discuss molecular, morphological and physiological aspects of the olfactory information processing in FXS models. We will highlight the decreased inhibitory/excitatory synaptic balance and the diminished synaptic plasticity found in this system resulting in behavioral alteration of individuals in the presence of odorant stimuli.