Tau; One Protein, So Many Diseases.

Tau, a member of the microtubule-associated proteins, is a known component of the neuronal cytoskeleton; however, in the brain tissue, it is involved in other vital functions beyond maintaining the cellular architecture. The pathologic tau forms aggregates inside the neurons and ultimately forms the neurofibrillary tangles. Intracellular and extracellular accumulation of different tau isoforms, including dimers, oligomers, paired helical filaments and tangles, lead to a highly heterogenous group of diseases named "Tauopathies". About twenty-six different types of tauopathy diseases have been identified that have different clinical phenotypes or pathophysiological characteristics. Although all these diseases are identified by tau aggregation, they are distinguishable based on the specific tau isoforms, the affected cell types and the brain regions. The neuropathological and phenotypical heterogeneity of these diseases impose significant challenges for discovering new diagnostic and therapeutic strategies. Here, we review the recent literature on tau protein and the pathophysiological mechanisms of tauopathies. This article mainly focuses on physiologic and pathologic tau and aims to summarize the upstream and downstream events and discuss the current diagnostic approaches and therapeutic strategies.

Oxidative damage of lysosomes in regulated cell death systems: Pathophysiology and pharmacologic interventions.

Lysosomes are small specialized organelles containing a variety of different hydrolase enzymes that are responsible for degradation of all macromolecules, entering the cells through the endosomal system or originated from the internal sources. This allows for transport and recycling of nutrients and internalization of surface proteins for antigen presentation as well as maintaining cellular homeostasis. Lysosomes are also important storage compartments for metal ions and nutrients. The integrity of lysosomal membrane is central to maintaining their normal function, but like other cellular membranes, lysosomal membrane is subject to damage mediated by reactive oxygen species. This results in spillage of lysosomal enzymes into the cytoplasm, leading to proteolytic damage to cellular systems and organelles. Several forms of lysosomal dependent cell death have been identified in diseases. Examination of these events are important for finding treatment strategies relevant to cancer or neurodegenerative diseases as well as autoimmune deficiencies. In this review, we have examined the current literature on involvement of lysosomes in induction of programed cell death and have provided an extensive list of therapeutic approaches that can modulate cell death. Exploitation of these mechanisms can lead to novel therapies for cancer and neurodegenerative diseases.

Preconditioned neurons with NaB and nicorandil, a favorable source for stroke cell therapy.

Poor survival of stem cells in the harsh microenvironment at the site of stroke, especially during acute phase of injury, remains a serious obstacle to achieve the desired prognosis. We hypothesized that combined treatment of neural stem cells (NSCs) with small molecules would precondition them to become robust and survive better as compared with the native nonpreconditioned cells. Mouse ganglionic NSCs were isolated, cultured, and characterized. The cells were preconditioned by treatment with sodium butyrate (NaB) and nicorandil (Nico) and transplanted in an experimentally induced stroke model. Sham-operated animals without treatment or animals with experimental stroke treated with basal medium, native NSCs, NSCs preconditioned with NaB or Nico alone were used as controls. The tissue samples and cells with different treatments were used to measure brain-tissue-derived neurotrophic factor (BDNF) level and the activity of phosphatidylinositol-3 kinase (PI3K), apurinic/apyrimidinic endonuclease 1 (APE1), and nuclear factor-κB (NF-κB) p50 both in vitro and in vivo, respectively. Additionally, survival of the cells and recovery indices for stroke were studied. The combined treatment with NaB + Nico resulted in increased BDNF level and higher PI3K, APE1, and the downstream NF-κB activation, which were blocked by pretreatment with their respective inhibitors. Donor cell survival increased postengraftment as assessed by 5-bromo-2'-deoxyuridine immunostaining and reduced Terminal deoxynucleotide transferase dUTP Nick End Labeling positivity at the site of engraftment. There was reduction in proinflammatory cytokines and infiltration of both GFAP + and CD68 + at the injury site. There was reduction in the infarct size and neurological function was preserved in the preconditioned cell treatment group. Our preconditioning approach with small molecules effectively improved the survival as well as functionality of NSCs.

Nicorandil potentiates sodium butyrate induced preconditioning of neurons and enhances their survival upon subsequent treatment with H2O2.

BACKGROUND: Extensive loss of donor neural stem cell (NSCs) due to ischemic stress and low rate of differentiation at the site of cell graft are two of the major issues that hamper optimal outcome in NSCs transplantation studies. Given that histone deacetylases (HDACs) modulate various cellular processes by deacetylating histones and non-histone proteins, we hypothesized that combined treatment with small molecules, sodium butyrate (NaB; a known HDAC inhibitor) and nicorandil, will enhance the rate neuronal differentiation of NSCs besides their preconditioning to resist oxidative stress. METHODS: NSCs derived from 14-day old Sprague Dawley rat ganglion eminence were characterized for tri-lineage differentiation. Treatment with 1 mM NaB significantly changed their culture characteristics while continuous treatment for 10 days enhanced their neural differentiation. NaB treatment also preconditioned the cells for their resistance to oxidative stress. RESULTS: The highest rate of neural differentiation and preconditioning effect was achieved when the NSCs were treated concomitantly with NaB and nicorandil. Cell proliferation assay showed that concomitant treatment with NaB and nicorandil retarded their rate of proliferation. CONCLUSION: These data conclude that preconditioning of NSCs with NaB and nicorandil effectively enhances their differentiation capacity besides preconditioning the cells to support their survival under ischemic conditions.

Optimization of time for neural stem cells transplantation for brain stroke in rats.

BACKGROUND: Despite encouraging data in terms of neurological outcome, stem cell based therapy for ischemic stroke in experimental models and human patients is still hampered by multiple as yet un-optimized variables, i.e., time of intervention, that significantly influence the prognosis. The aim of the present study was to delineate the optimum time for neural stem cells (NSCs) transplantation after ischemic stroke. METHODS: The NSCs were isolated from 14 days embryo rat ganglion eminence and were cultured in NSA medium (neurobasal medium, 2% B27, 1% N2, bFGF 10 ng/mL, EGF 20 ng/mL and 1% pen/strep). The cells were characterized for tri-lineage differentiation by immunocytochemistry for tubulin-III, Olig2 and GFAP expression for neurons, oligodendrocytes and astrocyte respectively. The NSCs at passage 3 were injected intraventricularly in a rodent model of middle-cerebral artery occlusion (MCAO) on stipulated time points of 1 & 12 h, and 1, 3, 5 and 7 days after ischemic stroke. The animals were euthanized on day 28 after their respective treatment. RESULTS: dUTP nick end labeling (TUNEL) assay and Caspase assay showed significantly reduced number of apoptotic cells on day 3 treated animals as compared to the other treatment groups of animals. The neurological outcome showed that the group which received NSCs 3 days after brain ischemia had the best neurological performance. CONCLUSIONS: The optimum time for NSCs transplantation was day 3 after ischemic stroke in terms of attenuation of ischemic zone expansion and better preserved neurological performance.