Purα regulates the induction of Znf179 transcription during neuronal differentiation.

Development of the mammalian central nervous system is an important process, which is accomplished through precise regulations of many different genes. Zinc finger protein 179 (Znf179) is one of the essential genes that plays a critical role in neuronal differentiation. In our previous study, Znf179 knockout mice displayed brain malformation and impaired brain functions. We have also previously shown that Znf179 involves in cell cycle regulation, but the regulatory mechanism of Znf179 expression is not yet fully characterized. Herein, we identified that Purα is an essential factor for the promotor activity of Znf179. We also showed concurrent expression of Znf179 and Purα during neuronal differentiation. We also found that overexpression of Purα increased Znf179 expression in neuronal differentiated P19 cells. Through its direct binding to Znf179, as shown using DAPA, Purα upregulates Znf179 expression, suggesting that Purα is important for the regulation of Znf179 expression during neuronal differentiation. Our data indicated that Purα is involved in the transcriptional regulation of Znf179 gene during neuronal differentiation, and is indispensable during the brain development.

miRNA-34c Overexpression Causes Dendritic Loss and Memory Decline.

Microribonucleic acids (miRNAs) play a pivotal role in numerous aspects of the nervous system and are increasingly recognized as key regulators in neurodegenerative diseases. This study hypothesized that miR-34c, a miRNA expressed in mammalian hippocampi whose expression level can alter the hippocampal dendritic spine density, could induce memory impairment akin to that of patients with Alzheimer's disease (AD) in mice. In this study, we showed that miR-34c overexpression in hippocampal neurons negatively regulated dendritic length and spine density. Hippocampal neurons transfected with miR-34c had shorter dendrites on average and fewer filopodia and spines than those not transfected with miR-34c (control mice). Because dendrites and synapses are key sites for signal transduction and fundamental structures for memory formation and storage, disrupted dendrites can contribute to AD. Therefore, we supposed that miR-34c, through its effects on dendritic spine density, influences synaptic plasticity and plays a key role in AD pathogenesis.

Autophagy activators rescue and alleviate pathogenesis of a mouse model with proteinopathies of the TAR DNA-binding protein 43.

TDP-43 is a multifunctional DNA/RNA-binding protein that has been identified as the major component of the cytoplasmic ubiquitin (+) inclusions (UBIs) in diseased cells of frontotemporal lobar dementia (FTLD-U) and amyotrophic lateral sclerosis (ALS). Unfortunately, effective drugs for these neurodegenerative diseases are yet to be developed. We have tested the therapeutic potential of rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR) and three other autophagy activators (spermidine, carbamazepine, and tamoxifen) in a FTLD-U mouse model with TDP-43 proteinopathies. Rapamycin treatment has been reported to be beneficial in some animal models of neurodegenerative diseases but not others. Furthermore, the effects of rapamycin treatment in FTLD-U have not been investigated. We show that rapamycin treatment effectively rescues the learning/memory impairment of these mice at 3 mo of age, and it significantly slows down the age-dependent loss of their motor function. These behavioral improvements upon rapamycin treatment are accompanied by a decreased level of caspase-3 and a reduction of neuron loss in the forebrain of FTLD-U mice. Furthermore, the number of cells with cytosolic TDP-43 (+) inclusions and the amounts of full-length TDP-43 as well as its cleavage products (35 kDa and 25 kDa) in the urea-soluble fraction of the cellular extract are significantly decreased upon rapamycin treatment. These changes in TDP-43 metabolism are accompanied by rapamycin-induced decreases in mTOR-regulated phospho-p70 S6 kinase (P-p70) and the p62 protein, as well as increases in the autophagic marker LC3. Finally, rapamycin as well as spermidine, carbamazepine, and tamoxifen could also rescue the motor dysfunction of 7-mo-old FTLD-U mice. These data suggest that autophagy activation is a potentially useful route for the therapy of neurodegenerative diseases with TDP-43 proteinopathies.

Atypical X-linked agammaglobulinaemia caused by a novel BTK mutation in a selective immunoglobulin M deficiency patient.

BACKGROUND: X-linked agammaglobulinaemia (XLA) is the most common inherited humoural immunodeficiency disorder. Mutations in the gene coding for Bruton's tyrosine kinase (BTK) have been identified as the cause of XLA. Most affected patients exhibit a marked reduction of serum immunoglobulins, mature B cells, and an increased susceptibility to recurrent bacterial infections. However, the diagnosis of XLA can be a challenge in certain patients who have near-normal levels of serum immunoglobulin. Furthermore, reports on XLA with renal involvement are scant. CASE PRESENTATION: We report an atypical XLA patient who presented with selective immunoglobulin M (IgM) immunodeficiency and nephropathy. He was diagnosed with selective IgM immunodeficiency, based on his normal serum immunoglobulin G (IgG) and immunoglobulin A (IgA) levels but undetectable serum IgM level. Intravenous immunoglobulin was initiated due to increased infections and persistent proteinuria but no improvement in proteinuria was found. A lupus-like nephritis was detected in his kidney biopsy and the proteinuria subsided after receiving a mycophenolate mofetil regimen. Although he had a history of recurrent bacterial infections since childhood, XLA was not diagnosed until B-lymphocyte surface antigen studies and a genetic analysis were conducted. CONCLUSIONS: We suggest that B-lymphocyte surface antigen studies and a BTK mutation analysis should be performed in familial patients with selective IgM deficiency to rule out atypical XLA.

MicroRNAs in Learning and Memory and Their Impact on Alzheimer's Disease.

Learning and memory formation rely on the precise spatiotemporal regulation of gene expression, such as microRNA (miRNA)-associated silencing, to fine-tune gene expression for the induction and maintenance of synaptic plasticity. Much progress has been made in presenting direct evidence of miRNA regulation in learning and memory. Here, we summarize studies that have manipulated miRNA expression using various approaches in rodents, with changes in cognitive performance. Some of these are involved in well-known mechanisms, such as the CREB-dependent signaling pathway, and some of their roles are in fear- and stress-related disorders, particularly cognitive impairment. We also summarize extensive studies on miRNAs correlated with pathogenic tau and amyloid-ß that drive the processes of Alzheimer's disease (AD). Although altered miRNA profiles in human patients with AD and in mouse models have been well studied, little is known about their clinical applications and therapeutics. Studies on miRNAs as biomarkers still show inconsistencies, and more challenges need to be confronted in standardizing blood-based biomarkers for use in AD.

Activation of a hippocampal CREB-pCREB-miRNA-MEF2 axis modulates individual variation of spatial learning and memory capability.

Phenotypic variation is a fundamental prerequisite for cell and organism evolution by natural selection. Whereas the role of stochastic gene expression in phenotypic diversity of genetically identical cells is well studied, not much is known regarding the relationship between stochastic gene expression and individual behavioral variation in animals. We demonstrate that a specific miRNA (miR-466f-3p) is upregulated in the hippocampus of a portion of individual inbred mice upon a Morris water maze task. Significantly, miR-466f-3p positively regulates the neuron morphology, function and spatial learning, and memory capability of mice. Mechanistically, miR-466f-3p represses translation of MEF2A, a negative regulator of learning/memory. Finally, we show that varied upregulation of hippocampal miR-466f-3p results from randomized phosphorylation of hippocampal cyclic AMP (cAMP)-response element binding (CREB) in individuals. This finding of modulation of spatial learning and memory via a randomized hippocampal signaling axis upon neuronal stimulation represents a demonstration of how variation in tissue gene expression lead to varied animal behavior.

HDAC1 dysregulation induces aberrant cell cycle and DNA damage in progress of TDP-43 proteinopathies.

TAR DNA-binding protein 43 (TDP-43) has been implicated in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-TDP) and amyotrophic lateral sclerosis. Histone deacetylase 1 (HDAC1) is involved in DNA repair and neuroprotection in numerous neurodegenerative diseases. However, the pathological mechanisms of FTLD-TDP underlying TDP-43 proteinopathies are unclear, and the role of HDAC1 is also poorly understood. Here, we found that aberrant cell cycle activity and DNA damage are important pathogenic factors in FTLD-TDP transgenic (Tg) mice, and we further identified these pathological features in the frontal cortices of patients with FTLD-TDP. TDP-43 proteinopathies contributed to pathogenesis by inducing cytosolic mislocalization of HDAC1 and reducing its activity. Pharmacological recovery of HDAC1 activity in FTLD-TDP Tg mice ameliorated their cognitive and motor impairments, normalized their aberrant cell cycle activity, and attenuated their DNA damage and neuronal loss. Thus, HDAC1 deregulation is involved in the pathogenesis of TDP-43 proteinopathies, and HDAC1 is a potential target for therapeutic interventions in FTLD-TDP.

The Role of Methylated Circulating Nucleic Acids as a Potential Biomarker in Alzheimer's Disease.

Previous studies report detection of high concentrations of circulating nucleic acids (CNAs), which are likely related to cell apoptosis, in the plasma of patients with cancers, stroke, trauma, and relapsing-remitting multiple sclerosis. However, the relationship between Alzheimer's disease (AD) and CNAs is unclear. A total of 36 adult participants (9 non-demented controls and 27 patients with AD) and patients with mild AD, who met the criteria for probable AD, were enrolled in the present study, which was conducted at the Department of Neurology of National Cheng Kung University Hospital. The CNA levels were increased in the plasma of patients with AD, culture medium of amyloid-ß-treated SH-SY5Y cells, and plasma from a mouse model of AD. The CNA concentrations in the plasma were positively correlated with the cognitive scores. Further, CNAs in patients with AD contained neuronal tissue-specific methylated LHX2, at CpG sites 1 and 5. These results showed that the increased levels of plasma CNAs could be related to neuronal cell death that was induced by ß-amyloid toxicity. Thus, the results suggested that the levels of plasma CNAs and LHX2 methylation might serve as potential biomarkers for the diagnosis of AD, particularly during the early stages of the disease.

G-CSF-mobilized Bone Marrow Mesenchymal Stem Cells Replenish Neural Lineages in Alzheimer's Disease Mice via CXCR4/SDF-1 Chemotaxis.

Recent studies reported granulocyte colony-stimulating factor (G-CSF) treatment can improve the cognitive function of Alzheimer's disease (AD) mice, and the mobilized hematopoietic stem cells (HSCs) or bone marrow mesenchymal stem cells (BM-MSCs) are proposed to be involved in this recovery effect. However, the exact role of mobilized HSC/BM-MSC in G-CSF-based therapeutic effects is still unknown. Here, we report that C-X-C chemokine receptor type 4 (CXCR4)/stromal cell-derived factor 1 (SDF-1) chemotaxis was a key mediator in G-CSF-based therapeutic effects, which was involved in the recruitment of repair-competent cells. Furthermore, we found both mobilized HSCs and BM-MSCs were able to infiltrate into the brain, but only BM-MSCs replenished the neural lineage cells and contributed to neurogenesis in the brains of AD mice. Together, our data show that mobilized BM-MSCs are involved in the replenishment of neural lineages following G-CSF treatment via CXCR4/SDF-1 chemotaxis and further support the potential use of BM-MSCs for further autogenically therapeutic applications.

Autophagy activation ameliorates neuronal pathogenesis of FTLD-U mice: a new light for treatment of TARDBP/TDP-43 proteinopathies.

The administration of rapamycin, an MTOR-dependent autophagy activator, for the treatment of neurodegenerative diseases has been tested in several animal models. Thus, whether autophagy activation would lead to the clearance of abnormal accumulation of aggregated proteins in neurodegenerative diseases is worthy of exploration. We have recently shown that rapamycin administration at the early pathological stage of a mouse model with frontotemporal lobar dementia (FTLD-U) characterized with cytoplasmic TARDBP/TDP-43(+)/ubiquitin(+) inclusions (UBIs) in the diseased neurons could rescue the learning/memory deficiency and the abnormal motor function disorder of the mice. This was accompanied by a decreased level of CASP3/caspase-3 and a reduction of the neuronal loss in the mouse forehead. Moreover, autophagy activation at a late pathological stage also could improve motor function, which was accompanied by a reduction of the TARDBP(+) UBIs. This study has set the principal for therapy of neurodegenerative diseases with the TARDBP protein, i.e., amyotrophic lateral sclerosis (ALS)-TDP and FTLD-TDP43, with the use of autophagy activators.