The Anti-Neuroinflammatory Effect of Extra-Virgin Olive Oil in the Triple Transgenic Mouse Model of Alzheimer's Disease.

Background: Chronic intake of extra virgin olive oil is beneficial for brain health and protects from age-related cognitive decline and dementia, whose most common clinical manifestation is Alzheimer's disease. Besides the classical pathologic deposits of amyloid beta peptides and phosphorylated tau proteins, another frequent feature of the Alzheimer's brain is neuroinflammation. Objective: In the current study, we assessed the effect that extra virgin olive oil has on neuroinflammation when administered to a mouse model of the disease. Methods: Triple transgenic mice were randomized to receive a diet enriched with extra virgin olive oil or regular diet for 8 weeks. At the end of this treatment period the expression level of several inflammatory biomarkers was assessed in the central nervous system. Results: Among the 79 biomarkers measured, compared with the control group, mice receiving the extra virgin olive oil had a significant reduction in MIP-2, IL-17E, IL-23, and IL-12p70, but an increase in IL-5. To validate these results, specific ELISA kits were used for each of them. Confirmatory results were obtained for MIP-2, IL-17E, IL-23, and IL-12-p70. No significant differences between the two groups were observed for IL-5. Conclusions: Our results demonstrate that chronic administration of extra virgin olive oil has a potent anti-neuroinflammatory action in a model of Alzheimer's disease. They provide additional pre-clinical support and novel mechanistic insights for the beneficial effect that this dietary intervention has on brain health and dementia.

FTDP-17 Mutations Alter the Aggregation and Microtubule Stabilization Propensity of Tau in an Isoform-Specific Fashion.

More than 50 different intronic and exonic autosomal dominant mutations in the tau gene have been linked to the neurodegenerative disorder frontotemporal dementia with Parkinsonism linked to chromosome-17 (FTDP-17). Although the pathological and clinical presentation of this disorder is heterogeneous among patients, the deposition of tau as pathological aggregates is a common feature. Collectively, FTDP-17 mutations have been shown to alter tau's ability to stabilize microtubules, enhance its aggregation, alter mRNA splicing, or induce its hyperphosphorylation, among other effects. Previous in vitro studies from our lab revealed that these mutations differ markedly from each other in the longest 2N4R isoform of tau. However, it is not entirely known whether the effect of a single mutation varies when compared between different isoforms of tau. Differences in the isoelectric points of the N-terminal region of tau isoforms lead to changes in their biochemical properties, raising the possibility that isoforms could also be disproportionately affected by disease-related mechanisms such as mutations. We therefore performed a comparative study of three FTDP-17 mutations present in different regions of tau (R5L, P301L, and R406W) in the three 4R isoforms of tau. We observed significant differences in the effect these mutations exert on the total amount and kinetics of aggregation, aggregate length distributions, and microtubule stabilizing propensity of 4R tau isoforms for all three selected mutants. These results demonstrate that different combinations of FTDP-17 mutations and tau isoforms are functionally distinct and could have important implications for our understanding of disease and animal models of tauopathies.

A Conserved Cytoskeletal Signaling Cascade Mediates Neurotoxicity of FTDP-17 Tau Mutations In Vivo.

The microtubule binding protein tau is strongly implicated in multiple neurodegenerative disorders, including frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), which is caused by mutations in tau. In vitro, FTDP-17 mutant versions of tau can reduce microtubule binding and increase the aggregation of tau, but the mechanism by which these mutations promote disease in vivo is not clear. Here we take a combined biochemical and in vivo modeling approach to define functional properties of tau driving neurotoxicity in vivo We express wild-type human tau and five FTDP-17 mutant forms of tau in Drosophila using a site-directed insertion strategy to ensure equivalent levels of expression. We then analyze multiple markers of neurodegeneration and neurotoxicity in transgenic animals, including analysis of both males and females. We find that FTDP-17 mutations act to enhance phosphorylation of tau and thus promote neurotoxicity in an in vivo setting. Further, we demonstrate that phosphorylation-dependent excess stabilization of the actin cytoskeleton is a key phosphorylation-dependent mediator of the toxicity of wild-type tau and of all the FTDP-17 mutants tested. Finally, we show that important downstream pathways, including autophagy and the unfolded protein response, are coregulated with neurotoxicity and actin cytoskeletal stabilization in brains of flies expressing wild-type human and various FTDP-17 tau mutants, supporting a conserved mechanism of neurotoxicity of wild-type tau and FTDP-17 mutant tau in disease pathogenesis.SIGNIFICANCE STATEMENT The microtubule protein tau aggregates and forms insoluble inclusion bodies known as neurofibrillary tangles in the brain tissue of patients with a variety of neurodegenerative disorders, including Alzheimer's disease. The tau protein is thus widely felt to play a key role in promoting neurodegeneration. However, precisely how tau becomes toxic is unclear. Here we capitalize on an "experiment of nature" in which rare missense mutations in tau cause familial neurodegeneration and neurofibrillary tangle formation. By comparing the biochemical activities of different tau mutations with their in vivo toxicity in a well controlled Drosophila model system, we find that all mutations tested increase phosphorylation of tau and trigger a cascade of neurotoxicity critically impinging on the integrity of the actin cytoskeleton.

Optimization of in vitro conditions to study the arachidonic acid induction of 4R isoforms of the microtubule-associated protein tau.

The microtubule-associated protein tau exists in six different isoforms that accumulate as filamentous aggregates in a wide spectrum of neurodegenerative diseases classified as tauopathies. One potential source of heterogeneity between these diseases could arise from differential tau isoform aggregation. in vitro assays employing arachidonic acid as an inducer of aggregation have been pivotal in gaining an understanding of the longest four repeat tau isoform (2N4R). These approaches have been less successful for modeling the shorter 1N4R and 0N4R tau isoforms in vitro. Through a careful analysis of in vitro conditions for aggregation, we found that the differences in the acidity of tau isoform N-terminal projection domains determine whether tau filaments cluster into larger assemblies in solution. Beyond the potential biological implications of filament clustering, we provide optimized conditions for the arachidonic acid induction of shorter 4R tau isoforms aggregation in vitro that greatly reduce filament clustering and improved modeling results.