T Lymphocytes and Inflammatory Mediators in the Interplay between Brain and Blood in Alzheimer’s Disease: Potential Pools of New Biomarkers

Alzheimer’s disease (AD) is a chronic neurodegenerative disorder and the main cause of dementia. The disease is among the leading medical concerns of the modern world, because only symptomatic therapies are available, and no reliable, easily accessible biomarkers exist for AD detection and monitoring. Therefore extensive research is conducted to elucidate the mechanisms of AD pathogenesis, which seems to be heterogeneous and multifactorial. Recently much attention has been given to the neuroinflammation and activation of glial cells in the AD brain. Reports also highlighted the proinflammatory role of T lymphocytes infiltrating the AD brain. However, in AD molecular and cellular alterations involving T cells and immune mediators occur not only in the brain, but also in the blood and the cerebrospinal fluid (CSF). Here we review alterations concerning T lymphocytes and related immune mediators in the AD brain, CSF, and blood and the mechanisms by which peripheral T cells cross the blood brain barrier and the blood-CSF barrier. This knowledge is relevant for better AD therapies and for identification of novel biomarkers for improved AD diagnostics in the blood and the CSF. The data will be reviewed with the special emphasis on possibilities for development of AD biomarkers

Tau Protein Modifications and Interactions: Their Role in Function and Dysfunction

Tau protein is abundant in the central nervous system and involved in microtubule assembly and stabilization. It is predominantly associated with axonal microtubules and present at lower level in dendrites where it is engaged in signaling functions. Post-translational modifications of tau and its interaction with several proteins play an important regulatory role in the physiology of tau. As a consequence of abnormal modifications and expression, tau is redistributed from neuronal processes to the soma and forms toxic oligomers or aggregated deposits. The accumulation of tau protein is increasingly recognized as the neuropathological hallmark of a number of dementia disorders known as tauopathies. Dysfunction of tau protein may contribute to collapse of cytoskeleton, thereby causing improper anterograde and retrograde movement of motor proteins and their cargos on microtubules. These disturbances in intraneuronal signaling may compromise synaptic transmission as well as trophic support mechanisms in neurons

Neuroplasticity and Neuroprotective Effect of Treadmill Training in the Chronic Mouse Model of Parkinson’s Disease

Physical training confers protection to dopaminergic neurons in rodent models of parkinsonism produced by neurotoxins. The sparing effect of physical training on dopaminergic neurons can be tested with training applied during chronic MPTP treatment, while the neurorestorative effect when training is applied after completing such treatment. In this study, the effect of the onset of training respective to chronic MPTP treatment was specifically addressed. Three groups of mice were injected with 10 doses of MPTP (12.5 mg/kg/injection) over 5 weeks. The first group remained sedentary; the second one underwent early onset training, which started 1 week before commencing MPTP treatment, continued throughout 5 weeks of treatment and 4 weeks thereafter; the third group underwent late-onset training of the same length and intensity as the former group, except that it started immediately after the end of MPTP treatment. Two groups served as controls: a saline-injected group that remained sedentary and saline-injected group, which underwent the same training as the early and late-onset training groups. Both early and late-onset physical training saved almost all nigral and VTA dopaminergic neurons, prevented inflammatory response, and increased the BDNF and GDNF levels to a similar extent. From these results one may conclude that early and late-onset training schedules were equipotent in their neuroprotective effect and that the mechanism of neuroprotection was similar. The sparing effect of early onset training may be satisfactorily explained by assuming that the increased level of BDNF and GDNF prevented the degeneration of dopaminergic neurons. To explain a similar number of dopaminergic neurons detected at the end of the early and late-onset training, one should additionally assume that the former training schedule induced neurogenesis. Results of this study support the view that physical activity may be neuroprotective even at a more advanced stage of PD and justify starting physical activity at any point of the disease

Pore-former enabled seeding of tau in rats:Alleviation by memantine and lithium chloride

Background: Tauopathies, including Alzheimer's disease (AD), are multifactorial diseases with strong phenotypic and genetic heterogeneity. Recent evidence revealed that mechanisms of pathogenesis of early (hereditary) and late (sporadic) forms of AD are different. This is not properly reflected in current experimental models, especially when it comes to sporadic forms of AD. Here, we present novel seeding based model and explore its suitability for therapeutic intervention.New method: We validate novel region specific approach to modelling Tau pathology reported by Koss and co-authors (2015). Wistar rats 3, 9 and 15 month-old were surgically prepared for hippocampal loading with pore-former polymeric 1,3-alkylpyridinium salts (Poly-APS) and recombinant human tau including pharmacological inhibition of phosphatase activity by okadaic acid co-administration. We explored whether tau seeding caused molecular and behavioural traits reminiscent of AD and explored their reversibility/prevention by administration of either memantine or lithium.Results: The presented model emulates several changes observed in progressive dementia such as: heightened levels of tau and its hyperphosphorylation, changes in tau compartmentalization, breakdown of the cytoskeleton, cognitive impairments, and sensitivity for anti-dementia treatment.Comparison with existing methods Seeding has been achieved in transgenic mouse models, but this is the first rat model significantly mimicking cognitive and neuronal changes akin to tauopathies. Moreover, we have successfully included the factor age in our model and can show sensitivity to drug treatment.Conclusions: These data validate a novel model of locally infused recombinant human Tau as an inducer of tauopathy in rats and holds the potential for development of novel therapies.</p

Induction of Brain Insulin Resistance and Alzheimer&rsquo;s Molecular Changes by Western Diet

The term Western diet (WD) describes the consumption of large amounts of highly processed foods, rich in simple sugars and saturated fats. Long-term WD feeding leads to insulin resistance, postulated as a risk factor for Alzheimer&rsquo;s disease (AD). AD is the main cause of progressive dementia characterized by the deposition of amyloid-&beta; (A&beta;) plaques and neurofibrillary tangles consisting of the hyperphosphorylated tau (p-Tau) protein in the brain, starting from the entorhinal cortex and the hippocampus. In this study, we report that WD-derived impairment in insulin signaling induces tau and A&beta; brain pathology in wild-type C57BL/6 mice, and that the entorhinal cortex is more sensitive than the hippocampus to the impairment of brain insulin signaling. In the brain areas developing WD-induced insulin resistance, we observed changes in p-Tau(Thr231) localization in neuronal subcellular compartments, indicating progressive tauopathy, and a decrease in amyloid precursor protein levels correlating with the appearance of A&beta; peptides. These results suggest that WD promotes the development of AD and may be considered not only a risk factor, but also a modifiable trigger of AD

Modulation of LPS-Induced Neurodegeneration by Intestinal Helminth Infection in Ageing Mice

Parasitic helminths induce a transient, short-term inflammation at the beginning of infection, but in persistent infection may suppress the systemic immune response by enhancing the activity of regulatory M2 macrophages. The aim of the study was to determine how nematode infection affects age-related neuroinflammation, especially macrophages in the nervous tissue. Here, intraperitoneal LPS-induced systemic inflammation resulting in brain neurodegeneration was enhanced by prolonged Heligmosomoides polygyrus infection in C57BL/6 mice. The changes in the brain coincided with the increase in M1 macrophages, reduced survivin level, enhanced APP and GFAP expression, chitin-like chains deposition in the brain and deterioration behaviour manifestations. These changes were also observed in transgenic C57BL/6 mice predisposed to develop neurodegeneration typical for Alzheimer’s disease in response to pathogenic stimuli. Interestingly, in mice infected with the nematode only, the greater M2 macrophage population resulted in better results in the forced swim test. Given the growing burden of neurodegenerative diseases, understanding such interactive associations can have significant implications for ageing health strategies and disease monitoring

Palm Oil-Rich Diet Affects Murine Liver Proteome and S-Palmitoylome

Palmitic acid (C16:0) is the most abundant saturated fatty acid in animals serving as a substrate in synthesis and &beta;-oxidation of other lipids, and in the modification of proteins called palmitoylation. The influence of dietary palmitic acid on protein S-palmitoylation remains largely unknown. In this study we performed high-throughput proteomic analyses of a membrane-enriched fraction of murine liver to examine the influence of a palm oil-rich diet (HPD) on S-palmitoylation of proteins. HPD feeding for 4 weeks led to an accumulation of C16:0 and C18:1 fatty acids in livers which disappeared after 12-week feeding, in contrast to an accumulation of C16:0 in peritoneal macrophages. Parallel proteomic studies revealed that HPD feeding induced a sequence of changes of the level and/or S-palmitoylation of diverse liver proteins involved in fatty acid, cholesterol and amino acid metabolism, hemostasis, and neutrophil degranulation. The HPD diet did not lead to liver damage, however, it caused progressing obesity, hypercholesterolemia and hyperglycemia. We conclude that the relatively mild negative impact of such diet on liver functioning can be attributed to a lower bioavailability of palm oil-derived C16:0 vs. that of C18:1 and the efficiency of mechanisms preventing liver injury, possibly including dynamic protein S-palmitoylation