Conditions of Alzheimer-type dementia in the old-old and oldest-old patients with special reference to extreme conditions of brain aging

A neuropathological study on 1540 consecutive autopsy brains ranging from 60 to 107 years of age revealed the following points. (1) Of the of the demented cases of the plaque-predominant type, 93% were complicated with multiple tiny cortical infarcts. They showed a tendency for dementia to develop before or after the appearance or worsening of a systemic disorder such as cardiovascular disease, respiratory infection and cancer. However, there was no case showing Alzheimer-type dementia (ATD). (2) The plaque-predominant type might be an extreme condition of brain aging in terms of senile plaques (SP). It is likely that although the pathological appearance of SP alone is not responsible for dementia, its coexistence with multiple cortical infarcts could be the cause of dementia. Therefore, this type should be distinguished from ATD. (3) Primary hippocampal degeneration could also be an extreme condition of brain aging in terms of neurofibrillary tangles. This condition was different pathologically from the hippocampal lesion in ATD. (4) Several characteristics of old-old and oldest-old patients were clarified.     

Effects of cromakalim (BRL 34915) on potassium conductances in CA3 neurons of the guinea-pig hippocampus in vitro

Summary The action of the potassium channel activator, cromakalim (BRL 34915), on membrane potential, input resistance and current-voltage-relationship of CA3 neurons in a slice preparation of the guinea-pig hippocampus was investigated by means of intracellular recordings. In the presence of tetrodotoxin, cromakalim (30–100 mol/l) produced a hyperpolarization up to 4 mV associated with a decrease in input resistance up to 10 MOhms. Determination of the equilibrium potential of the cromakalim action revealed that the hyperpolarization is due to the activation of a potassium conductance. This cromakalim-activated potassium conductance was voltage-dependent, i.e. it increased with hyperpolarization. Among a number of potassium channel blockers tested, only Cs⁺ (2 mmol/l) and Ba²⁺ (0.5 mmol/1) were able to inhibit the cromakalim-induced effects. Simultaneously, both cations suppressed the hyperpolarizing inward rectification (anomalous rectification) in these neurons, indicating that cromakalim activated or potentiated an inwardly rectifying potassium conductance. In addition, cromakalim slightly enhanced both amplitude and duration of afterhyperpolarizations following single calcium-dependent action potentials, suggesting that cromakalim might have a weak facilitatory effect on calcium-dependent potassium conductances.Send offprint requests to C. Alzheimer at the above address     

Subthreshold oscillations generated by TTX-sensitive sodium currents in dorsal cochlear nucleus pyramidal cells

During intracellular recordings in rodent brainstem slice preparations, dorsal cochlear nucleus (DCN) pyramidal cells (PCs) exhibit characteristic discharge patterns to depolarizing current injection that depend on the membrane potential from which the responses are evoked. When depolarized from hyperpolarized potentials, PCs can respond with a short-latency action potential followed by a long silent interval (pauser) or a train of action potentials with a long latency (buildup). During the silent intervals in a pauser or a buildup response, the membrane potential slowly depolarizes towards spike threshold, often exhibiting distinct voltage oscillations of 1–2 mV before the first spike. The subthreshold voltage oscillations were investigated using whole cell recordings from DCN PCs in rat pup (P10–14) brainstem slices. The oscillations were unaffected by excitatory and inhibitory neurotransmitter antagonists, and were not temporally locked to the onset of the depolarization. The oscillations typically became larger as spike threshold was approached, and had a characteristic frequency between 40 and 100 Hz. In the presence of tetrodotoxin (TTX, 500 nM), the oscillations were significantly suppressed, and could not be evoked at any voltage below or above spike threshold. The oscillations were not blocked by phenytoin or Cd²⁺, but they were affected by prior activity in the neuron for approximately 1 s. We conclude that voltage-gated Na⁺ channels are required to generate membrane oscillations during the buildup phase. We suggest that the subthreshold oscillations play a role in controlling spike timing in PCs when the membrane potential slowly approaches, or hovers near, spike threshold.     

衰老时海马神经元树突的可塑性增生

用形态计量的方法对老年(30个月)和成年(17个月)大鼠脑(Golgi染色标本)的海马CA3区锥体细胞的树突分支进行分级计数和测量了终末支的长度。结果是CA3神经元基树突和顶树突共有9级分支,衰老时第4级和第9级分支有显著的增多(P<0.02,P<0.03)。基树突终末支的长度衰老时无明显改变,顶树突终末支长度较成年组增加(P<0.05)。提示衰老时海马神经元的树突仍具有一定的增生和分化能力。这可能是对神经元退变的一种代偿机制。     

NMDAR1单克隆抗体抑制谷氨酸诱导的大鼠海马神经元Ca2+内流

目的观察人N-甲基-D-门冬氨酸受体(NMDAR,NR)主亚基(NR1)单克隆抗体mAbN1对谷氨酸诱导的大鼠海马神经元Ca2 内流的影响。方法建立谷氨酸介导的大鼠海马神经元兴奋毒性损伤模型,以mAbN1及MK-801分别预处理海马神经元,用Fluo-3/AM法,在激光扫描共聚焦显微镜下观察对细胞内游离Ca2 浓度([Ca2 ]i)的影响。结果mAbN1能显著抑制谷氨酸所致海马神经元[Ca2 ]i升高,此作用强于MK-801,且其本身对生理状态下神经元[Ca2 ]i无影响。结论mAbN1的抗兴奋毒性作用可能是通过改变NR的蛋白质二级结构从而影响兴奋毒性作用中的Ca2 内流实现的。     

Bilateral Occlusion of Carotid Artery in Awake Hypertensive Rats (SHR-SP) as a Model of Global Cerebral Ischemia

Bilateral occlusion of carotid arteries in awake hypertensive rats (SHR-SP) was used as a model of global brain ischemia (duration of occlusion — until appearance of seizures). In normotensive rats (WKY), no seizures developed over 60 min. We revealed swelling of mitochondria in dendrites of hippocampal CA1 pyramidal cells, which was more pronounced in SHP-SP than in WKY rats. Blood pressure and heart rate in SHR-SP rats increased starting from the first minutes of occlusion, while in WKY rats these parameters remained unchanged. We proved that bilateral occlusion of the carotid arteries in awake SHR-SP rats can be used as an adequate model of global cerebral ischemia. Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 146, No. 12, pp. 627–630, December, 2008     

癫痫大鼠海马结构谷氨酸和nNOS神经元的动态变化

的：探讨谷氨酸(Glu)和一氧化氮(NO)二者在癫痫模型中的作用及其相关性。方法：戊四唑化学点燃癫痫大鼠，分为Ⅰ、Ⅲ、Ⅴ级组和Ⅴ级后24h组。采用免疫组织化学方法和图像分析技术。结果：(1)Ⅲ、Ⅴ级组Glu免疫反应阳性神经元数目和平均光密度值升高；但Ⅴ级比Ⅲ级组有所下降；Ⅴ级后24h组恢复到对照组水平。(2)Ⅴ级组和Ⅴ级后24h组nNOS免疫反应阳性神经元数目和平均光密度值升高。结论：戊四唑点燃癫痫模型中，随着点燃级别的进展，Glu的含量是呈先增加后减少的趋势，而NO的含量是逐渐增加的，提示二者在癫痫发作中既有相关性又有独立性。     

Analysis of behavioral and hippocampal variation in congenic albino and pigmented BALB mice

Mice of the BALB/c strain are widely used in behavioral research in spite of the albino condition, which can obscure brain-behavior relationships. We have developed a pigmented BALB strain, congenic to BALB/c, which could be more appropriate for neurogenetic studies that aim at identifying the effects of neurological mutations on behavior. Comparison of inbred albino and pigmented congenic BALB arising from the same litters provides a valuable tool for detecting the consequences of the albino mutation on behavioral performances. Preliminary results presented here show that the albino condition does not interfere with the development and patterns of connectivity of mossy fibers in the hippocampus. On the other hand, obvious coat color-linked differences appear for locomotor activity and defecation scores in the open field, pigmented mice being unexpectedlyl less active and more reactive than albino, as if better vision increased their reactions to a novel, anxiogenic environment. Finally, pigmented mice do not show better performances in the radial maze, which confirms that the inability of BALB mice for spatial learning in a highly demanding version of this task cannot be attributed to their inability to process visual information.     

Adenosine receptor density and the depression of evoked neuronal activity in the rat hippocampus in vitro

The relationship between the heterogeneous distribution of A-1 adenosine receptors and the capacity of adenosine to depress neuronal activity was examined in the rat hippocampus. Utilizing autoradiographic techniques, the distribution of A-1 adenosine receptors was assessed by the binding of [3H]cyclohexyladenosine ([3H]CHA) to cryostat sections of rat brain. The apical dendritic region of CA1 showed a differential distribution of adenosine receptors between the stratum radiatum and stratum lacunosum/moleculare. The physiological relevance of this binding difference was studied in the hippocampal slice by examining the capacity of adenosine to depress evoked potentials in these two strata. It was observed that the receptor differences correlated with differential sensitivities to adenosine modulation of the evoked potentials. These data suggest that receptor density, as shown by binding techniques, may provide not only a qualitative but also a quantitative map of the sites of adenosine action.     

OGD增加小鼠离体海马组织内cPKCβII和nPKCε的膜转位

目的:通过观察无糖低氧(OGD)刺激对小鼠海马脑片内蛋白激酶C(PKC)特定亚型膜转位水平(激活程度)的影响,进一步证实我们在整体低氧预适应小鼠模型上所获实验结果,并为离体海马脑片缺血/低氧预适应(I/HPC)模型建立及后续药物干预实验打下基础。方法:急性分离小鼠海马组织、制备400!μm厚度的脑片,并用无糖低氧(OGD)人工脑脊液(ACSF)模拟缺血/低氧刺激;应用SDS-PAGE和Westernbolt等生化技术,并结合GelDoc凝胶成像系统,半定量检测OGD刺激2、5、10、15和30min后海马脑片内cPKCβII和nPKCε的膜转位水平。结果:OGD刺激可增高海马脑片内cPKCβII和nPKCε的膜转位水平,且这种增高从刺激5min开始持续至30min均有显著差异(P<0.001,n=6)。结论:实验结果进一步证实cPKCβII和nPKCε可能参与脑缺血/低氧性预适应的形成过程,并提示OGD10min作为制备离体海马脑片I/HPC模型的预处理刺激较为合理。