Knockdown of lncRNA TUG1 inhibits hippocampal neuronal apoptosis and participates in aerobic exercise-alleviated vascular cognitive impairment.

OBJECTIVES: Our previous study indicated that aerobic exercise relieves cognitive impairment in patients with vascular cognitive impairment (VCI) via regulating brain-derived neurotrophic factor (BDNF), but the mechanism is not yet clear. This study aimed to explore whether lncRNA taurine upregulated gene 1 (TUG1) participates in the process of VCI by regulating BDNF. METHODS: The expressions of TUG1 and BDNF in the serum of VCI patients were detected. The potential molecular mechanisms of TUG1 in regulating hippocampal neuronal apoptosis were explored in oxygen and glucose deprivation-induced (OGD-induced) hippocampal cell line HT22. The VCI mouse model was established, and TUG1 and BDNF were overexpressed via lentivirus injection. The cognitive impairment of mice was detected by the Morris water maze experiment after the aerobic exercise. RESULTS: The level of TUG1 was elevated in the serum of VCI patients compared with the control group. The knockdown of TUG1 in OGD-induced HT22 cells increased BDNF level and decreased cell apoptosis, and the downregulation of BDNF restored the decreased cell apoptosis. RNA immunoprecipitation and RNA pull-down assays showed that TUG1 could bind to BDNF protein. The aerobic exercise alleviated cognitive impairment and inhibited hippocampal apoptosis in VCI mice. Meanwhile, the overexpression of TUG1 reversed the therapeutic effects of aerobic exercise on cognitive impairment. CONCLUSIONS: The knockdown of TUG1 reduced hippocampal neuronal apoptosis and participates in the aerobic exercise-alleviated VCI, which was partly through regulating BDNF.

A Novel Targeted and High-Efficiency Nanosystem for Combinational Therapy for Alzheimer's Disease.

Alzheimer's disease (AD) remains the most prevalent neurodegenerative disease, and no effective treatment is available yet. Metal-ion-triggered aggregates of amyloid-beta (Aß) peptide and acetylcholine imbalance are reported to be possible factors in AD pathogenesis. Thus, a combination therapy that can not only inhibit and reduce Aß aggregation but also simultaneously regulate acetylcholine imbalance that can serve as a potential treatment for AD is needed. Here, clioquinol (metal-ion chelating agent) and donepezil (acetylcholinesterase (AChE) inhibitor) co-encapsulated human serum albumin (HSA) nanoparticles (dcHGT NPs) are designed, which are modified with transcriptional activator protein (TAT) and monosialotetrahexosylganglioside (GM1). The GM1 lipid and TAT peptide endow this drug delivery nanosystem with high brain entry efficiency and long-term retention capabilities through intranasal administration. It is found that dcHGT NPs can significantly inhibit and eliminate Aß aggregation, relieve acetylcholine-related inflammation in microglial cells, and protect primary neurons from Aß oligomer-induced neurotoxicity in vitro. The alleviation of Aß-related inflammation and AChE-inhibited effect further synergistically adjust acetylcholine imbalance. It is further demonstrated that dcHGT NPs reduce Aß deposition, ameliorate neuron morphological changes, rescue memory deficits, and greatly improve acetylcholine regulation ability in vivo. This multifunctional synergetic nanosystem can be a new candidate to achieve highly efficient combination therapy for AD.

Knockdown of lncRNA TUG1 inhibits hippocampal neuronal apoptosis and participates in aerobic exercise-alleviated vascular cognitive impairment

OBJECTIVES: Our previous study indicated that aerobic exercise relieves cognitive impairment in patients with vascular cognitive impairment (VCI) via regulating brain-derived neurotrophic factor (BDNF), but the mechanism is not yet clear. This study aimed to explore whether lncRNA taurine upregulated gene 1 (TUG1) participates in the process of VCI by regulating BDNF. METHODS: The expressions of TUG1 and BDNF in the serum of VCI patients were detected. The potential molecular mechanisms of TUG1 in regulating hippocampal neuronal apoptosis were explored in oxygen and glucose deprivation-induced (OGD-induced) hippocampal cell line HT22. The VCI mouse model was established, and TUG1 and BDNF were overexpressed via lentivirus injection. The cognitive impairment of mice was detected by the Morris water maze experiment after the aerobic exercise. RESULTS: The level of TUG1 was elevated in the serum of VCI patients compared with the control group. The knockdown of TUG1 in OGD-induced HT22 cells increased BDNF level and decreased cell apoptosis, and the downregulation of BDNF restored the decreased cell apoptosis. RNA immunoprecipitation and RNA pull-down assays showed that TUG1 could bind to BDNF protein. The aerobic exercise alleviated cognitive impairment and inhibited hippocampal apoptosis in VCI mice. Meanwhile, the overexpression of TUG1 reversed the therapeutic effects of aerobic exercise on cognitive impairment. CONCLUSIONS: The knockdown of TUG1 reduced hippocampal neuronal apoptosis and participates in the aerobic exercise-alleviated VCI, which was partly through regulating BDNF.

Functional protection of learning and memory abilities in rats with vascular dementia.

PURPOSE: The present study clarified the effects of repetitive transcranial magnetic stimulation (rTMS) in rats with vascular dementia (VaD) and explored the underlying mechanisms. METHODS: Two-vessel occlusion was used as a VaD model. Two weeks after carotid artery occlusion, high (5 Hz) or low (1 Hz) frequency rTMS were applied for 10 days. Spatial learning and memory abilities were tested with a Morris water maze. Hippocampal CA1 neurons were histologically examined. The expressions of mammalian target of rapamycin (mTOR) and eukaryotic initiation factor 4E (eIF-4E) in CA1 were detected by western blot, and immunohistochemistry. RESULTS: Unlike unlesioned control animals, VaD rats had an impaired morphology of CA1 neurons and a reduced ability of spatial memory. rTMS significantly improved both, the morphology and the learning and memory abilities of VaD rats compared to untreated lesioned rats. Protein expressions of mTOR and eIF-4E in CA1 of VaD rats were lower than in control rats but rTMS significantly increased the expression compared to untreated VaD rats. CONCLUSIONS: rTMS promotes recovery of learning and memory abilities of VaD rats. Molecular analysis suggests that the beneficial effect of rTMS may be partly induced by upregulation of protein expressions of mTOR and eIF-4E in CA1.

The restoration after repetitive transcranial magnetic stimulation treatment on cognitive ability of vascular dementia rats and its impacts on synaptic plasticity in hippocampal CA1 area.

The purposes of this research were to study the restoration on the cognitive ability of rat models with vascular dementia (VaD) by repetitive transcranial magnetic stimulation (rTMS) treatment and its impacts on synaptic plasticity in hippocampal CA1 area and to further explore the molecular mechanisms of the rTMS treatment on vascular dementia. Thirty-six male Wistar rats were randomly divided into four groups: the normal control group, the vascular dementia model group, the low-frequency rTMS group, and the high-frequency rTMS group. Two-vessel occlusion was employed to make VaD models. Low-frequency rTMS group rats were treated with 0.5 Hz rTMS for 6 weeks. High-frequency rTMS group rats underwent 5 Hz rTMS for 6 weeks. Morris water maze was carried out to detect the ability of spatial learning and memory of rats. The ultra-structural changes of synapses in four groups were observed by transmission electron microscope. Then the expressions of brain-derived neurotrophic factor (BDNF), NMDAR1, and Synaptophysin (SYN) mRNA and proteins in hippocampal CA1 area were determined by real-time PCR, western blot, and immunohistochemistry assay. After rTMS treatment, the learning and memory abilities of VaD rats improved significantly. The ultra-structures of synapses in hippocampal CA1 area in rTMS groups were reformed. The mRNA and protein expressions of BDNF, NMDAR1, and SYN in the low-frequency rTMS group and in the high-frequency rTMS group were higher than that in VaD model group (P < 0.05). rTMS plays an important and beneficial role in the restoration treatment of vascular dementia, which may be related to the mechanism that rTMS can increase the mRNA and protein expressions of BDNF, NMDAR1, and SYN and affect the synaptic plasticity in hippocampal CA1 area.

Coherence Characteristics of Gamma-band EEG during rest and cognitive task in MCI and AD.

The aim of this study is to investigate whether EEG coherence during different functional states facilitates the detection of AD-related EEG changes; and which brain regions these changes were. The EEGs in both rest and performing the cognitive task states of 3 groups was recorded for coherence measure. The 3 groups are the mild cognitive impairment (MCI) group, Alzheimer's disease(AD) and the healthy control group. In rest state, coherence value of EEG for AD group was lower than that in other two groups in channel pairs of Fp2-T4, F4-C4 (P<0.01) and F3-C3, Fp1-T3, P3-O1 (P<0.05). There was no significant difference between the MCI and control. In cognitive performing state (counting the target number), coherence of EEGs in all channel connections for AD group were lower compared with MCI and control group. Furthermore, in Fp2-T4 (prefrontal-temporal) and F4-C4(frontal-central) pairs, MCI showed significant lower coherence than that in control. The conclusion of this study was that the coherence of EEG would seem to be a useful and more sensitive indicator for cognitive impairment in cognitive performing state than that in rest, and AD patient showed coherence abnormal changes in more regions in this state. The abnormal localization also suggested the AD-related cognitive impairment maybe commence with frontal activity abnormality and then spread to the other brain regions.