The toxin MPTP generates similar cognitive and locomotor deficits in hTau and tau knock-out mice.

Parkinson's disease (PD) is characterized by motor deficits, although cognitive disturbances are frequent and have been noted early in the disease. The main pathological characteristics of PD are the loss of dopaminergic neurons and the presence of aggregated α-synuclein in Lewy bodies of surviving cells. Studies have also documented the presence of other proteins within Lewy bodies, particularly tau, a microtubule-associated protein implicated in a wide range of neurodegenerative diseases, including Alzheimer's disease (AD). In AD, tau pathology correlates with cognitive dysfunction, and tau mutations have been reported to lead to dementia associated with parkinsonism. However, the role of tau in PD pathogenesis remains unclear. To address this question, we induced parkinsonism by injecting the toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in hTau mice, a mouse model of tauopathy expressing human tau, and a mouse model knock-out for tau (TKO). We found that although MPTP impaired locomotion (gait analysis) and cognition (Barnes maze), there were no discernable differences between hTau and TKO mice. MPTP also induced a slight but significant increase in tau phosphorylation (Thr205) in the hippocampus of hTau mice, as well as a significant decrease in the soluble and insoluble tau fractions that correlated with the loss of dopaminergic neurons in the brainstem. Overall, our findings suggest that, although MPTP can induce an increase in tau phosphorylation at specific epitopes, tau does not seem to causally contribute to cognitive and locomotor deficits induced by this toxin.

Deletion of the Fanconi Anemia C Gene in Mice Leads to Skeletal Anomalies and Defective Bone Mineralization and Microarchitecture.

Fanconi anemia (FA) is a rare genetic disorder associated with a progressive decline in hematopoietic stem cells leading to bone marrow failure. FA is also characterized by a variety of developmental defects including short stature and skeletal malformations. More than half of children affected with FA have radial-ray abnormalities, and many patients have early onset osteopenia/osteoporosis. Although many Fanconi anemia genes have been identified and a molecular pathway defined, the underlying mechanism leading to bone defects remains elusive. To understand the role of FA genes in skeletal development and bone microarchitecture, we evaluated bone physiology during embryogenesis and in adult FancA- and FancC-deficient mice. We found that both FancA-/- and FancC-/- embryos have abnormal skeletal development shown by skeletal malformations, growth delay, and reduced bone mineralization. FancC-/- adult mice present altered bone morphology and microarchitecture with a significant decrease in cortical bone mineral density in a sex-specific manner. Mechanical testing revealed that male but not female FancC-/- mice show reduced bone strength compared with their wild-type littermates. Ex vivo cultures showed that FancA-/- and FancC-/- bone marrow-derived mesenchymal stem cells (BM MSC) have impaired differentiation capabilities together with altered gene expression profiles. Our results suggest that defective bone physiology in FA occurs in utero and possibly results from altered BM MSC function. These results provide valuable insights into the mechanism involved in FA skeletal defects. © 2018 American Society for Bone and Mineral Research.

Differential effects of voluntary treadmill exercise and caloric restriction on tau pathogenesis in a mouse model of Alzheimer's disease-like tau pathology fed with Western diet.

BACKGROUND: Tau is a microtubule-associated protein that becomes pathological when it undergoes hyperphosphorylation and aggregation as seen in Alzheimer's disease (AD). AD is mostly sporadic, with environmental, biological and/or genetic risks factors, interacting together to promote the disease. In the past decade, reports have suggested that obesity in midlife could be one of these risk factors. On the other hand, caloric restriction and physical exercise have been reported to reduce the incidence and outcome of obesity as well as AD. METHODS: We evaluated the impact of voluntary physical exercise and caloric restriction on tau pathology during 2months in hTau mice under high caloric diet in order to evaluate if these strategies could prevent AD-like pathology in obese conditions. RESULTS: We found no effects of obesity induced by Western diet on both Tau phosphorylation and aggregation compared to controls. However, exercise reduced tau phosphorylation while caloric restriction exacerbated its aggregation in the brains of obese hTau mice. We then examined the mechanisms underlying changes in tau phosphorylation and aggregation by exploring major tau kinases and phosphatases and key proteins involved in autophagy. However, there were no significant effects of voluntary exercise and caloric restriction on these proteins in hTau mice that could explain our results. CONCLUSION: In this study, we report differential effects of voluntary treadmill exercise and caloric restriction on tau pathogenesis in our obese mice, namely beneficial effect of exercise on tau phosphorylation and deleterious effect of caloric restriction on tau aggregation. Our results suggest that lifestyle strategies used to reduce metabolic disorders and AD must be selected and studied carefully to avoid exacerbation of pathologies.

Insulin deprivation induces PP2A inhibition and tau hyperphosphorylation in hTau mice, a model of Alzheimer's disease-like tau pathology.

Abnormally hyperphosphorylated tau aggregated as intraneuronal neurofibrillary tangles is one of the two neuropathological hallmarks of Alzheimer's disease (AD). The majority of AD cases are sporadic with numerous environmental, biological and genetic risks factors. Interestingly, insulin dysfunction and hyperglycaemia are both risk factors for sporadic AD. However, how hyperglycaemia and insulin dysfunction affect tau pathology, is not well understood. In this study, we examined the effects of insulin deficiency on tau pathology in transgenic hTau mice by injecting different doses of streptozotocin (STZ), a toxin that destroys insulin-producing cells in the pancreas. One high dose of STZ resulted in marked diabetes, and five low doses led to a milder diabetes. Both groups exhibited brain tau hyperphosphorylation but no increased aggregation. Tau hyperphosphorylation correlated with inhibition of Protein Phosphatase 2A (PP2A), the main tau phosphatase. Interestingly, insulin injection 30 minutes before sacrifice partially restored tau phosphorylation to control levels in both STZ-injected groups. Our results confirm a link between insulin homeostasis and tau phosphorylation, which could explain, at least in part, a higher incidence of AD in diabetic patients.

High-fat, high-sugar, and high-cholesterol consumption does not impact tau pathogenesis in a mouse model of Alzheimer's disease-like tau pathology.

Aggregates of hyperphosphorylated tau protein are a pathological hallmark of Alzheimer's disease (AD). The origin of AD is multifactorial, and many metabolic disorders originating from overconsumption of fat, cholesterol, and sugar are associated with higher risk of AD later in life. However, the effects of fat, cholesterol, and sugar overconsumption on tau pathology in AD remain controversial. Using the hTau mice, a model of AD-like tau pathology, we assessed the effects of high-fat, high-cholesterol, and/or high-sugar diets on tau pathogenesis. Surprisingly, we found no effects of these compounds, even combined, on tau phosphorylation, O-GlcNAcylation, splicing, cleavage, and aggregation, suggesting that their overconsumption does not seem to worsen tau pathology in these mice.

ERK (MAPK) does not phosphorylate tau under physiological conditions in vivo or in vitro.

Alzheimer's disease is characterized by the deposition of intracellular aggregates of hyperphosphorylated tau protein. Tau hyperphosphorylation has been attributed in part to the deregulation of kinases and phosphatases activities. Extracellular signal regulated-kinases 1/2 (ERK1/2) were reported to be activated in the first stages of Alzheimer's disease and were proposed as a potential therapeutic target. However, although the phosphorylation of tau by ERK1/2 has been demonstrated in cell-free system, it remains controversial in vivo. Here, we showed that pharmacologic inhibition of ERK1/2 in mice and SH-SY5Y cells did not reduce basal levels of phospho-tau or hypothermia-induced tau hyperphosphorylation. We also found that activating ERK1/2 by hyperthermia did not correlate with increased tau phosphorylation. Finally, ERK1/2 was inhibited, but tau phosphorylation was not altered in Mek1-/- mice. In conclusion, these results do not support the involvement of ERK1/2 in tau phosphorylation under physiological conditions.