Hyperbaric oxygen therapy activates CREB/BDNF signaling pathway to reduce synaptic damage in hippocampal neurons of Alzheimer disease mice

AIM To investigate the effect of hyperbaric oxygen (HBO) on synaptic damage of hippocampal neurons in APP/PS1 transgenic (TG) mice and its possible mechanism. METHODS The 6-month-old male APP/PS1 TG mice were randomly divided into TG group, HBO group and cAMP response element binding protein (CREB) inhibitor H89 group, with 10 mice in each group. Ten male wild-type (WT) C57BL/6 mice of the same age were used as negative control group (WT group). The mice in HBO and H89 groups were treated with HBO for 6 cycles, while the mice in WT group and TG group were not treated. The learning and memory abilities were observed by Morris water maze. The nesting ability of the mice was detected by nesting test. The Nissl bodies in hippocampal neurons were observed by Nissl staining. The mRNA expression of CREB and brain-derived neurotrophic factor (BDNF) in hippocampus was detected by real-time PCR. The protein levels of synapsin (SYN), postsynaptic density protein 95 (PSD95), growth-associated protein 43 (GAP43), CREB, phosphorylated CREB (p-CREB) and BDNF in the hippocampus were determined by Western blot. RESULTS Compared with WT group, the learning and memory abilities of the mice in TG group were signilficantly reduced (P<0.05). In addition, the nesting score, the number of Nissl bodies in the hippocampal neurons, the mRNA expression of CREB and BDNF, and the protein levels of SYN, PSD95, GAP43, p-CREB and BDNF were also decreased significantly (P<0.05). Compared with TG group, the learning and memory abilities of the mice in HBO group were improved (P<0.05). Meanwhile, the nesting scores of the mice were significantly increased (P<0.05), the neurons in the hippocampus were arranged neatly, and the number of Nissl bodies, the relative mRNA expression of CREB and BDNF,and the protein levels of SYN, PSD95, GAP43, p-CREB and BDNF were also increased significantly (P<0.05). Compared with HBO group, the mice in H89 group had poor learning and memory abilities, lowered nesting scores and decreased number of Nissl bodies. Futhermore, the relative mRNA expression of CREB and BDNF, and the protein levels of SYN, PSD95, GAP43, p-CREB and BDNF were also decreased significantly (P<0.05). CONCLUSION HBO improves the learning and memory abilities of APP/PS1 TG mice, and its mechanism may be related to activating the CREB/BDNF signaling pathway to reduce synaptic damage of hippocampal neurons in mice.     

Neuroprotective effect of novel Rho kinase inhibitor FSD-C10 on a mouse model of Alzheimer disease

AIM: To explore the neuroprotective effect of novel Rho kinase inhibitor FSD-C10 on Alzheimer disease (AD) model of APP/PS1 double transgenic (Tg) mice. METHODS: Male APP/PS1 Tg mice (n=20) at 8 months of age were randomly divided into 2 groups:model group and FSD-C10 treatment group. The mice were treated with normal saline or FSD-C10 (25 mg·kg^-1·d^-1) by intraperitoneal injection, once daily for 2 months. Age-and sex-matched wild-type (WT) mice without treatment were used as the control. The Morris water maze (MWM) test and SMART 3.0 behavioral record system were applied to examine and analyze the spatial cognitive function of the mice. The protein levels and distribution of Aβ, p-tau and synapse-associated proteins such as synaptophysin, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and postsynaptic density protein 95 (PSD-95) were determined by immunofluorescence staining. The protein levels of phosphorylated amyloid precursor protein at Thr668[p-APP(Thr668)], beta-site APP-cleaving enzyme 1 (BACE1) and synapse-associated proteins in the brain were analyzed by Western blot. RESULTS: Compared with model group, FSD-C10 treatment significantly improved the cognitive function of the APP/PS1 Tg mice, accompanied by reduced Aβ deposition and p-tau level, increased protein level of p-APP (Thr668) in the central nervous system, decreased expression of BACE1, and increased expression of synapse-associated proteins in the brain of the mice (P<0.05). CONCLUSION: FSD-C10 has neuroprotective potential in the APP/PS1 Tg mice. The mechanism may be related to enhancing the non-amyloidogenic APP cleavage pathway, reducing the production of Aβ oligomers, the deposition of senile plaques and the amount of tau protein, up-regulating synapse-associated proteins, and increasing synaptic plasticity.     

PSMB7基因与阿尔茨海默病的相关性研究

目的探讨蛋白酶体亚基-B7（PSMB7）基因多态性、载脂蛋白E（ApoE）基因多态性和阿尔茨海默病（AD）的相关性。方法 376例日本AD患者（324例迟发型和52例早发型AD）和378例非痴呆对照组中,用TaqMan-PCR法检测PSMB7基因rs7871785（＋561G/A）、rs3780199（＋26651C/T）及APOE基因的单核苷酸多态性,并分析与AD的相关性。结果 PSMB7基因rs7871785 A/A纯合子频率在早发型AD中明显高于对照组（0.75 vs 0.60,P=0.037）,而rs3780199 C/C纯合子频率在AD中明显高于对照组（0.23 vs 0.15,P=0.009）。在非APOE-ε4携带者中,AD患者rs3780199 C/C纯合子频率明显高于对照组（0.23 vs 0.16,P=0.005）。结论 PSMB7基因rs7871785多态位点A/A纯合子与早发型AD存在相关性,而rs3780199C/C纯合子独立于APOE-ε4基因与迟发型AD存在相关性。     

Basic fibroblast growth factor and Alzheimer's disease

Alzheimer's disease (AD), which is one type of senile deimentia,has three remarkable pathologic characteristics-senile plaque, neurofibrillar tangles and neuronal death. As a neurotrophic factor, basic fibroblast growth factor (bFGF) is closely related to AD. This art icle reviewed the interaction between bFGF and AD-associated gene products (such as amyliod protein, presenilin, apoloprotein E and microtubulin-associated protein tau) and neuronal apoptosis. Some researchers suggested that bFGF may be put forward as potential therapeutic agent in AD and play a role in preventing or retarding the pathological process of this disease, alleviating or even eradicat ing the pathological insults of this disease.     

茯苓水提液对小鼠学习记忆的影响

目的研究中药茯苓水提液对小鼠学习记忆的影响．方法通过跳台法观察茯苓水提液对东莨菪碱所致记忆获得障碍模型小鼠和30％乙醇所致记忆再现障碍模型小鼠的影响．结果1）茯苓水提液能减少东莨菪碱所致记忆获得障碍模型小鼠5min内学习及记忆实验的错误次数,延长潜伏期,P＜0．05,P＜0．01,差异有统计学意义．2）茯苓水提液能减少30％乙醇所致记忆再现障碍模型小鼠测试实验中5rain内错误次数,延长潜伏期,P＜0．05,P＜0．01,差异有统计学意义．结论茯苓水提液能改善化学药物所致学习记忆障碍模型小鼠的学习记忆能力．     

Effects of Aβ1-42-induced microglial cells on survival of neural stem cells in vitro

AIM: To explore the effects of β-amyloid protein 1-42 (Aβ_1-42)-induced microglia on the survival of cultured neural stem cells (NSCs) in vitro . METHODS: Using the Transwell chambers to build a coculture system of NSCs and microglia, we detected the proliferation, differentiation and apoptosis of the NSCs with the microglia before and after induction by Aβ_1-42. RESULTS: Compared with non-intervention group, the proliferation rate of NSCs in Aβ_1-42 intervention coculture group decreased, as well as the positive expression rates of microtubule-associated protein 2 (MAP-2) and choline acetyltransferase. CONCLUSION: The inflammation mediated by Aβ_1-42 inhib their the proliferation of NSCs and induces their apoptosis. Inflammation also significantly reduces the ratio of NSCs differentiating to neurons, especially to cholinergic neurons.     

Protective effect of folate and vitamin B12 on Alzheimer-like pathological changes in brain of aged rats with hyperhomocysteinemia

AIM:To explore the effect of hyperhomocysteinemia on the Alzheimer-like pathological changes in the brain of aged rat. METHODS:The rats were treated with homocysteine(Hcy) by intravenous injection through vena caudalis with or without a simultaneous supplementation of folate and Vitamin B₁₂(FB) in the drinking water for 28 weeks. The distribution and aggregation of tau protein were detected by Bielschowsky silver staining. Western blotting was used to determine the protein levels of tau phosphorylation, glycogen synthase kinase 3β(GSK-3β) and protein phosphatase 2A(PP2A). RESULTS:Treatment with Hcy induced hyperhomocysteinemia in aged rats and resulted in the formation of neurofibrillary tangles in the brain. Supplementation of FB effectively reduced the tangles. Hyperhomocysteinemia also induced Alzheimer-like tau hyperphosphorylation at multiple sites(Ser^199/202and Ser³⁹⁶). Hyperhomocysteinemia activated GSK-3β and inhibited the activity of PP2A. Supplementation of FB alleviated the changes of tau and the activities of GSK-3β and PP2A. CONCLUSION:Supplementation of FB ameliorates the hyperhomocysteinemia-induced Alzheimer-like pathological changes of tau protein possibly through regulating the activity of GSK-3β and PP2A in aged rats.     

Involvement of extracellular signal regulated kinase in the regulation of amyloid precursor protein processing in PC12 cells by TPPB

AIM: To explore the signal transduction pathways involved in the regulation of amyloid precursor protein (APP) processing by protein kinase C (PKC) activator TPPB.METHODS: PC12 cells were treated with TPPB (PKC activator) for 3 h and various signal transduction inhibitors were added to the conditioned medium to investigate their effects on α-secretase form of soluble amyloid precursor protein (sAPPα) secretion after TPPB treatment via Western blotting. Extracellular signal regulated kinase (ERK, p42/44MAPK) and phospho-p42/44MAPK were also measured after TPPB treatment.RESULTS: TPPB (1 μmol/L) significantly increased sAPPα secretion as compared with control group. The increase in sAPPα secretion by TPPB was partially blocked by ERK inhibitor U0126, c-Jun N-terminal kinase (JNK) inhibitor SP600125 and protein tyrosine kinase (PTK) inhibitor genistein, but not by p38MAPK inhibitor SB203580. TPPB (1 μmol/L) increased the expression of phospho-p42/44MAPK without altering total p42/44MAPK levels.CONCLUSION: ERK, JNK and PTK may be involved in the regulation of APP processing by TPPB.     

灵芝三萜单体细胞保护与自噬诱导活性比较

比较不同灵芝三萜单体对PCI2细胞保护和自噬诱导活性的差异。结果表明,灵芝酸A、B、C、C2、DM、K对H2O2诱导的细胞损伤最大保护率分别为32．83％、12．63％、53．03％、30．30％、2．53％和25．25％;对Aβ25-35诱导的细胞损伤最大保护率分剐为6．74％、29．02％、23．81％、25．07％、10．15％和5．12％;自噬诱导最大阳性率分别达到22．33％、32．67％、35．50％、28．33％、11．83％和29．50％。不同灵芝三萜单体的活性也有明显的差异,且各单体在不同活性方面均未表现出一致的强弱关系。     

Gait deficits in liver disease: Hepatic encephalopathy and hepatic myelopathy

In this issue, the unusual clinical presentation of a horse diagnosed is described with severe liver cirrhosis and hepatic encephalopathy. The horse initially presented for thoracic and pelvic limb ataxia and weakness, and signs of forebrain disease were not apparent until later in the disease process. The typical pathology of central nervous system disease associated with liver disease is related to encephalopathy and forebrain disease; however, the spinal cord is occasionally also involved. Hepatic myelopathy is a rare syndrome usually associated with surgical or acquired portosystemic shunts, liver cirrhosis and/or portal hypertension in man. Where a gliopathy is the most prominent pathological feature seen in hepatic encephalopathy, in hepatic myelopathy the most remarkable feature is demyelination of the corticospinal tracts of the distal cervical and thoracic spinal cord with occasional axon loss. The clinical signs of hepatic myelopathy are spastic paresis/paralysis with normal sensory findings and preserved sphincter function. The prognosis for hepatic myelopathy is generally poor. In summary, in severe liver disease, motor deficits can occur secondary to the encephalopathy, but motor deficits can also occur as a result of spinal cord pathology such as seen in hepatic myelopathy. In examination of horses with myelopathies, liver disease as a cause of myelopathy should be included in our list of differentials.