阿尔茨海默病转基因小鼠早期记忆功能障碍与氧化应激损伤关系的实验研究

Objective To investigate the spatial learning and memory ability,the changes of indicators of oxidative stress,and their relationship in transgenic APP/PS1 mouse model of Alzheimer's disease(APP/PS1 mice). Methods The spatial learning and memory ability were assessed by Morris water maze test,and the activity or content of SOD, GSH-PX, MDA, and protein carbonyl in brain tissues were measured by ELISA in the APP/PS1 and wild type (WT) mice. Furthermore, the relationship between the learning and memory performances and the indicators of oxidative stress was examined. Results No significant difference in the spatial learning was observed between the APP/PS1 and WT mice (P ＜0. 05). The spatial memory which was measured as the percentage of time traveling in the targeted quadrant to the total traveling time was significantlydeclined in the APP/PS1 mice(29. 02 ± 4. 27) % as compared with the WT mice(47. 39 ± 6. 01) %(t =0. 000 ,P ＜0. 05). The percentage of length of traveling in the targeted quadrant to the total length traveled was significantly lower in the APP/PS1 mice(28. 85 ±3.77)% compared with the WT mice(46. 70 ±5.60)% (t =0. 000,P ＜0. 05). These findings indicated that the spatial learning and memory ability of APP/PS1 mice was significantly decreased compared to WT mice. There was no significant difference in activity or content of SOD,GSH-PX,and MDA in brain tissues between the APP/PS1 and WT mice (P ＜ 0. 05), while the content of protein carbonyl was significantly elevated in the APP/PS1 mice (2. 67 ±0. 19) than in the WT mice (2. 38 ±0. 15)(t = 0. 008, P ＜ 0. 05). Correlation analysis revealed that the elevated protein carbonyl was negatively correlated with the percentage of length traveled in the targeted quadrant(r = - 0. 639, P ＜ 0. 05) and the percentage of time traveled in the targeted quadrant(r = - 0. 636 ,P ＜ 0. 05). Conclusion The spatial memory impairment was negatively correlated with the elevated protein carbonyl in the APP/PS1 mice, suggesting that protein carbonylation caused by oxidative stress might play an important role in the development of memory impairment in the early stage of Alzheimer's disease.     

阿尔茨海默病转基因小鼠早期记忆功能障碍与氧化应激损伤关系的实验研究

目的 观察转APP/PS1基因阿尔茨海默病(AD)小鼠(APP/PS1小鼠)早期空间学习记忆功能及相关氧化应激反应指标的变化,并探讨它们之间的相关性.方法 应用Morris水迷宫评定APP/PS1小鼠及相应野生型(WT)小鼠的空间学习记忆功能,采用ELISA方法检测脑组织中超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-PX)活性以及丙二醛(MDA)和蛋白质羰基的含量,并进行相关性分析.结果 2组小鼠的空间学习能力无明显差异(P＞0.05),而APP/PS1小鼠在目标象限(定位航行实验中平台所置第二象限)中航行时间占总时间的百分比(29.02±4.27)%较WT小鼠(47.39±6.01)%显著下降(t=0.000,P＜0.05),APP/PS1小鼠在目标象限中航行路程占总路程的百分比(28.85±3.77)%较WT小鼠(46.70±5.60)%也显著下降(t=0.000,P＜0.05),提示APP/PS1小鼠的空间记忆功能较WT小鼠显著下降.2组小鼠脑组织中的MDA含量、SOD和GSH-PX活性均无明显差异(P均＞0.05),而APP/PS1小鼠脑组织中的蛋白质羰基含量(2.67±0.19)较WT小鼠(2.38±0.15)显著增加(t=0.0088,P＜0.05).相关性分析表明:APP/PS1小鼠蛋白质羰基含量与目标象限航行时间百分比呈显著负性相关(r=-0.639,P＜0.05),APP/PS1小鼠蛋白质羰基含量与目标象限航行路程百分比呈显著负性相关(r=-0.636,P＜0.05).结论 APP/PS1小鼠早期空间记忆功能损害与脑组织中的蛋白质羰基含量升高呈负性相关,提示氧化应激导致的蛋白质羰基化在AD早期记忆损害发病过程中具有重要作用.

Abstract：

Objective To investigate the spatial learning and memory ability,the changes of indicators of oxidative stress,and their relationship in transgenic APP/PS1 mouse model of Alzheimer's disease(APP/PS1 mice). Methods The spatial learning and memory ability were assessed by Morris water maze test,and the activity or content of SOD, GSH-PX, MDA, and protein carbonyl in brain tissues were measured by ELISA in the APP/PS1 and wild type (WT) mice. Furthermore, the relationship between the learning and memory performances and the indicators of oxidative stress was examined. Results No significant difference in the spatial learning was observed between the APP/PS1 and WT mice (P ＜0. 05). The spatial memory which was measured as the percentage of time traveling in the targeted quadrant to the total traveling time was significantlydeclined in the APP/PS1 mice(29. 02 ± 4. 27) % as compared with the WT mice(47. 39 ± 6. 01) %(t =0. 000 ,P ＜0. 05). The percentage of length of traveling in the targeted quadrant to the total length traveled was significantly lower in the APP/PS1 mice(28. 85 ±3.77)% compared with the WT mice(46. 70 ±5.60)% (t =0. 000,P ＜0. 05). These findings indicated that the spatial learning and memory ability of APP/PS1 mice was significantly decreased compared to WT mice. There was no significant difference in activity or content of SOD,GSH-PX,and MDA in brain tissues between the APP/PS1 and WT mice (P ＜ 0. 05), while the content of protein carbonyl was significantly elevated in the APP/PS1 mice (2. 67 ±0. 19) than in the WT mice (2. 38 ±0. 15)(t = 0. 008, P ＜ 0. 05). Correlation analysis revealed that the elevated protein carbonyl was negatively correlated with the percentage of length traveled in the targeted quadrant(r = - 0. 639, P ＜ 0. 05) and the percentage of time traveled in the targeted quadrant(r = - 0. 636 ,P ＜ 0. 05). Conclusion The spatial memory impairment was negatively correlated with the elevated protein carbonyl in the APP/PS1 mice, suggesting that protein carbonylation caused by oxidative stress might play an important role in the development of memory impairment in the early stage of Alzheimer's disease.     

Memantine improves spatial learning in a transgenic mouse model of Alzheimer's disease

Memantine, a low- to moderate-affinity uncompetitive N-methyl-D-aspartate receptor antagonist, has been shown to improve learning and memory in several pharmacological models of Alzheimer's disease (AD). In the present study, the effect of memantine on locomotor activity, social behavior, and spatial learning was assessed in a transgenic mouse model of AD. Eight-month-old male C57BL/6J mice carrying mutated human APP and PS1 genes (APP/PS1) and their nontransgenic (NT) litter mates were administered a therapeutic dose of memantine (30 mg/kg/day p.o.) for 2 to 3 weeks. At this age, APP/PS1 mice show elevated levels of beta-amyloid peptides in several brain regions. APP/PS1 mice exhibited less exploratory rearing and increased aggressive behavior compared with NT mice. In the water maze test for spatial learning, APP/PS1 mice had longer escape latencies to both hidden and visible platforms, but they did not differ from NT mice in their swimming speed. Memantine significantly improved the acquisition of the water maze in APP/PS1 mice without affecting swimming speed. Memantine did not affect either locomotor activity or aggressive behavior in either genotype. These data indicate that memantine improves hippocampus-based spatial learning in a transgenic mouse model of AD without producing nonspecific effects on locomotion/exploratory activity.     

Nobiletin, a citrus flavonoid, reverses learning impairment associated with N-methyl-D-aspartate receptor antagonism by activation of extracellular signal-regulated kinase signaling

Recent studies have indicated that learning-induced activation of extracellular signal-regulated kinase (ERK) signaling via N-methyl-D-aspartate (NMDA) receptors is required for consolidation of the resultant learning. These findings raise an idea that control of ERK signaling may be a potential target for treatment of cognitive dysfunction. Our recent studies have demonstrated that nobiletin, a polymethoxylated flavone from Citrus depressa, enhances cAMP/protein kinase A/ERK signaling in cultured rat hippocampal neurons and PC12D cells. Here, we, for the first time, present the evidence that this natural compound reverses learning impairment associated with NMDA receptor antagonism by activation of ERK in the hippocampus. Treatment with 50 mg/kg nobiletin reversed the NMDA receptor antagonist MK-801 (dizocilpine maleate)-induced learning impairment in mice. Western blot analysis also showed that nobiletin reversed MK-801-induced inhibition of learning-associated ERK activation in the hippocampus of the animals. Furthermore, consistent with these results, in cultured rat hippocampal neurons, nobiletin restored MK-801-induced impairment of NMDA-stimulated phosphorylation of ERK in a concentration-dependent manner. Taken together, the present study suggests that compounds that activate ERK signaling improve cognitive deficits associated with NMDA receptor hypofunction and that nobiletin may give us a new insight into therapeutic drug development for neurological disorders exhibiting cognitive impairment accompanied by a hypofunction of NMDA receptor-ERK signaling.     

转基因阿尔茨海默病小鼠脑内炎症反应的诱发因素研究

目的 观察炎症反应在转基因阿尔茨海默病(AD)小鼠脑组织中的变化,探讨AD脑内炎症反应的诱发因素.方法 选用3、12个月龄转人β-淀粉样前体蛋白/早老素-1(APP/PS1)基因AD小鼠及正常野生型(WT)小鼠,分别应用免疫组织化学法和ELISA法观察脑内淀粉样斑块、炎性因子[白细胞介素(IL)-1β、IL-6、肿瘤坏死因子(TNF)α、前列腺素(PGE)2]的变化.结果 3个月龄APP/PS1基因AD小鼠脑组织中无淀粉样斑块沉积,未发现激活的星型胶质细胞和小胶质细胞,炎性因子IL-1β、IL-6、TNFα、PGE2的含量与WT小鼠差异无统计学意义(P均＞0.05).12个月龄转APP/PS1基因AD小鼠脑组织中有大量淀粉样斑块沉积,并伴有大量激活的星型胶质细胞和小胶质细胞,炎性因子IL-1β、IL-6、TNFα、PGE2的含量[分别为(56.02±9.04)、(8.66±0.83)、(97.48±26.58)、(72.18±21.01)ng/g]较WT小鼠[分别为(29.81±6.03)、(7.73±0.74)、(61.98±11.11)、(37.23±10.96)ng/g]及3个月龄转APP/PS1基因AD小鼠[分别为(30.05±3.53)、(7.43±1.17)、(59.34±10.47)、(42.56±5.93)ng/g]显著增加(P＜0.05或P＜0.01).结论 在淀粉样斑块形成之前,转APP/PS1基因AD小鼠脑组织中无明确的炎症反应;而淀粉样斑块沉积之后,脑组织中有显著的炎症反应;AD脑内炎症反应与淀粉样斑块形成密切相关,淀粉样蛋白(Aβ)沉积是导致脑内炎症反应的直接诱发因素.

Abstract：

Objective To observe the changes of cerebral inflammation-related markers in brain of a transgenic mouse model of Alzheimer's disease (AD) ,and to determine the causative factor to the development of cerebral inflammation in AD. Methods 3- and 12-month-old β-amyloid protein precursor ( APP)/presenilin (PSI) transgenic mice and age-matched wild-type mice (WT) were used in the study. The changes of amyloid plaques, inflammatory factors ( interleukin 1β ( IL-1β ); interleukin 6( IL-6 ); tumor necrosis factor α (TNFα) ;prostaglandin E2 (PGE2)) in the brains among these mice were measured by immunohistochemistry and ELISA. Results Immunohistochemical analysis revealed that no amyloid plaques and activated astrocytes as well as microglia were observed in the 3-month-old APP/PS1 mice. There were no significant differences in the levels of inflammatory factors (IL-1β, IL-6 ,TNFα,and PGE2) between the 3-month-old APP/PS1 and WT mice ( Ps ＞ 0. 05 ). However, abundant amyloid plaques accompanied by a remarkable increase of activated astrocytes and microglia were found in the brain of the 12-month-old APP/PS1 mice. The levels of inflammatory factors (IL-1β,IL-6,TNFα, and PGE2 ) were significantly increased in the 12-month-old APP/PS1 mice ([56. 02 ±9. 04] ng/g, [8. 66 ±0.83] ng/g, [97.48 ±26.58] ng/g, [72. 18 ±21.01] ng/g) than in the WT mice ([29. 18 ± 6. 03] ng/g, [7. 73 ± 0. 74] ng/g, [61.98 ±11.11] ng/g, [37. 23 ± 10. 96] ng/g) and the 3-month-old APP/PS1 mice ( [30. 05 ± 3.53] ng/g, [7.43 ± 1.17] ng/g, [59.34 ± 10. 07] ng/g, [42. 56 ±5.93] ng/g) (P＜0.05,or P＜0.01,respectively). Conclusion This study demonstrates that the APP/PS1mice did not show cerebral inflammation before the appearance of amyloid plaques, and exhibited remarkable inflammation after amyloid plaque deposition. These findings suggest that the induction of cerebral inflammation is tightly associated with amyloid plaque formation, and deposition of amyloid-beta protein (Aβ) may be the direct causative factor to the development of cerebral inflammation in AD.     

A neuronal microtubule-interacting agent, NAPVSIPQ, reduces tau pathology and enhances cognitive function in a mouse model of Alzheimer's disease

Neurofibrillary tangles composed of aggregated, hyperphosphorylated tau in an abnormal conformation represent one of the major pathological hallmarks of Alzheimer's disease (AD) and other tauopathies. However, recent data suggest that the pathogenic processes leading to cognitive impairment occur before the formation of classic tangles. In the earliest stages of tauopathy, tau detaches from microtubules and accumulates in the cytosol of the somatodendritic compartment of cells. Either as a cause or an effect, tau becomes hyperphosphorylated and aggregates into paired helical filaments that comprise the tangles. To assess whether an agent that modulates microtubule function can inhibit the pathogenic process and prevent cognitive deficits in a transgenic mouse model with AD-relevant tau pathology, we administered the neuronal tubulin-preferring agent, NAPVSIPQ (NAP). Three months of treatment with NAP at an early-to-moderate stage of tauopathy reduced the levels of hyperphosphorylated soluble and insoluble tau. A 6-month course of treatment improved cognitive function. Although nonspecific tubulin-interacting agents commonly used for cancer therapy are associated with adverse effects due to their anti-mitotic activity, no adverse effects were found after 6 months of exposure to NAP. Our results suggest that neuronal microtubule interacting agents such as NAP may be useful therapeutic agents for the treatment or prevention of tauopathies.     

Memory impairment and awareness of memory deficits in early-stage Alzheimer's disease

In addition to their memory impairment, individuals with Alzheimer's disease (AD) often suffer from deficits in self-awareness. Awareness of memory deficits or metamemory is a multifaceted function, comprising on-line self-monitoring, generalized self-beliefs of memory efficacy, and generalized knowledge about memory functions. Awareness of memory problems in early-stage AD is a matter of clinical importance from a humanistic point of view, because higher levels of awareness may be associated with better future outcomes. Current methods of measuring awareness tend to fall into two categories, i.e., to introduce a questionnaire assessing patient/caregiver discrepancies; or to ask a patient to prospectively predict or retrospectively postdict their own memory performances. Characteristics of each measure as well as relationship between the two measures were discussed. For the performance prediction/postdiction paradigm, we used recognition memory of auditory verbal learning tests and awareness of memory deficits were examined in 24 individuals with early-stage AD. In addition to their significantly impaired recognition memory, individuals with AD displayed underawareness of memory deficits even at this early stage. They retrospectively overestimated memory performance after actual performance, but appeared to benefit from feedback and displayed intact on-line awareness of memory dysfunction, leading to normal prediction of the second session. However, individuals with AD again failed to retrospectively incorporate incidents of memory failure into generalized self-belief systems. Brain/behavior correlational analyses suggest that the prefrontal cortex and posterior dorsomedial regions including the precuneus may be involved in self-awareness.     

Valproic acid inhibits Abeta production, neuritic plaque formation, and behavioral deficits in Alzheimer's disease mouse models

Neuritic plaques in the brains are one of the pathological hallmarks of Alzheimer's disease (AD). Amyloid β-protein (Aβ), the central component of neuritic plaques, is derived from β-amyloid precursor protein (APP) after β- and γ-secretase cleavage. The molecular mechanism underlying the pathogenesis of AD is not yet well defined, and there has been no effective treatment for AD. Valproic acid (VPA) is one of the most widely used anticonvulsant and mood-stabilizing agents for treating epilepsy and bipolar disorder. We found that VPA decreased Aβ production by inhibiting GSK-3β–mediated γ-secretase cleavage of APP both in vitro and in vivo. VPA treatment significantly reduced neuritic plaque formation and improved memory deficits in transgenic AD model mice. We also found that early application of VPA was important for alleviating memory deficits of AD model mice. Our study suggests that VPA may be beneficial in the prevention and treatment of AD.     

Verbal episodic memory impairment in Alzheimer's disease: a combined structural and functional MRI study

Anatomical and functional MRI images were acquired in a group of healthy elderly subjects (n = 11) and a group of patients diagnosed with probable Alzheimer's disease, from mild to moderate severity (n = 8). During functional sessions, verbal episodic Encoding and Recognition tasks were presented to subjects. Both groups were compared in terms of gray matter volume and cerebral activation. Furthermore, in the AD group, correlations between hippocampal gray matter volume and whole-brain activations were examined. When compared to healthy controls, AD patients presented significant gray matter atrophy as well as reduced activations during Encoding and Recognition in the medial temporal lobes and inferior parietal/superior temporal associative areas. In the same regions, the fMRI activity elicited by the Recognition task was positively correlated with hippocampal gray matter volume. Moreover, an increase of left prefrontal activity during Encoding and Recognition was observed in AD patients relative to controls and was correlated with memory performance. This additional activity elicited by episodic memory processes was not found to correlate with the degree of medial temporal atrophy in our group of patients. Our study shows that function in brain regions critical to episodic memory is altered in AD. During episodic Recognition, these functional changes may closely correlate with the progressive structural changes observed in the hippocampal region.     

G-CSF rescues the memory impairment of animal models of Alzheimer's disease

Most of the current clinical treatments for Alzheimer's disease (AD) are largely symptomatic and can have serious side effects. We have tested the feasibility of using the granulocyte colony-stimulating factor (G-CSF), which is known to mobilize hematopoietic stem cells (HSCs) from the bone marrow into the peripheral blood, as a therapeutic agent for AD. Subcutaneous administration of G-CSF into two different beta-amyloid (Abeta)-induced AD mouse models substantially rescued their cognitive/memory functions. The rescue was accompanied by the accumulation of 5-bromo-2'deoxyuridine-positive HSCs, as well as local neurogenesis surrounding the Abeta aggregates. Furthermore, the level of acetylcholine in the brains of Tg2576 mice was considerably enhanced upon G-CSF treatment. We suggest that G-CSF, a drug already extensively used for treating chemotherapy-induced neutropenia, should be pursued as a novel, noninvasive therapeutic agent for the treatment of AD.     

帕金森病模型大鼠的学习记忆功能障碍

目的:利用Morris水迷宫对帕金森病模型大鼠的学习记忆障碍进行分析评价,为帕金森病的早期诊断及记忆障碍的治疗提供依据。方法:实验于2004-05/2005-04在安徽省立医院神经干细胞移植实验室及安徽医科大学神经生物学教研室完成。①筛选:制作帕金森病模型之前淘汰有记忆障碍的大鼠及有旋转行为的大鼠。②模型制备:采用立体定向技术建立6-羟多巴诱发的帕金森病大鼠模型。③检测指标:通过Morris水迷宫实验测定模型1个月时及3个月时大鼠寻找平台潜伏期、游泳距离、游泳速度、120s内在各象限游泳距离占总距离百分比。结果:共纳入实验大鼠74只,①淘汰了有记忆障碍、游泳时原地转圈及不成功模型共33只。最后纳入实验41只大鼠。帕金森病模型1个月组15只,帕金森病模型3个月组16只,对照组10只。②对照组大鼠与帕金森病模型1个月组大鼠游泳速度比较差异存在显著性(P<0.05)。帕金森病模型1个月组与3个月组比较差异不显著(P>0.05)。③帕金森病模型大鼠游泳距离明显增加,与对照组比较差异显著(P<0.05)。④对照组平台象限的距离与其他象限比较差异显著(P<0.05)。帕金森病模型1,3个月组各象限的游泳距离比较差异无显著性。结论:帕金森病模型大鼠表现出渐进的空间记忆能力和搜索策略的损害,与早期帕金森病患者表现的工作记忆损害相似。     

帕金森病模型大鼠的学习记忆功能障碍

目的：利用Morris水迷宫对帕金森病模型大鼠的学习记忆障碍进行分析评价，为帕金森病的早期诊断及记忆障碍的治疗提供依据。 方法：实验于2004-05／2005—04在安徽省立医院神经干细胞移植实验室及安徽医科大学神经生物学教研室完成。①筛选：制作帕金森病模型之前淘汰有记忆障碍的大鼠及有旋转行为的大鼠。②模型制备：采用立体定向技术建立6-羟多巴诱发的帕金森病大鼠模型。③检测指标：通过Morris水迷宫实验测定模型1个月时及3个月时大鼠寻找平台潜伏期、游泳距离、游泳速度、120s内在各象限游泳距离占总距离百分比。 结果：共纳入实验大鼠74只，①淘汰了有记忆障碍、游泳时原地转圈及不成功模型共33只。最后纳入实验41只大鼠。帕金森病模型1个月组15只，帕金森病模型3个月组16只，对照组10只。②对照组大鼠与帕金森病模型1个月组大鼠游泳速度比较差异存在显著性（P〈0．05）。帕金森病模型1个月组与3个月组比较差异不显著（P〉0．05）。③帕金森病模型大鼠游泳距离明显增加，与对照组比较差异显著（P〈0．05）。④对照组平台象限的距离与其他象限比较差异显著（P〈0．05）。帕金森病模型1，3个月组各象限的游泳距离比较差异无显著性。 结论：帕金森病模型大鼠表现出渐进的空间记忆能力和搜索策略的损害．与早期帕金森病患者表现的工作记忆损害相似。     

CNI-1493 inhibits Abeta production, plaque formation, and cognitive deterioration in an animal model of Alzheimer's disease

Alzheimer's disease (AD) is characterized by neuronal atrophy caused by soluble amyloid beta protein (Abeta) peptide "oligomers" and a microglial-mediated inflammatory response elicited by extensive amyloid deposition in the brain. We show that CNI-1493, a tetravalent guanylhydrazone with established antiinflammatory properties, interferes with Abeta assembly and protects neuronal cells from the toxic effect of soluble Abeta oligomers. Administration of CNI-1493 to TgCRND8 mice overexpressing human amyloid precursor protein (APP) for a treatment period of 8 wk significantly reduced Abeta deposition. CNI-1493 treatment resulted in 70% reduction of amyloid plaque area in the cortex and 87% reduction in the hippocampus of these animals. Administration of CNI-1493 significantly improved memory performance in a cognition task compared with vehicle-treated mice. In vitro analysis of CNI-1493 on APP processing in an APP-overexpressing cell line revealed a significant dose-dependent decrease of total Abeta accumulation. This study indicates that the antiinflammatory agent CNI-1493 can ameliorate the pathophysiology and cognitive defects in a murine model of AD.     

Quantitative in vivo measurement of early axonal transport deficits in a triple transgenic mouse model of Alzheimer's disease using manganese-enhanced MRI

Impaired axonal transport has been linked to the pathogenic processes of Alzheimer's disease (AD) in which axonal swelling and degeneration are prevalent. The development of non-invasive neuroimaging methods to quantitatively assess in vivo axonal transport deficits would be enormously valuable to visualize early, yet subtle, changes in the AD brain, to monitor the disease progression and to quantify the effect of drug intervention. A triple transgenic mouse model of AD closely resembles human AD neuropathology. In this study, we investigated age-dependent alterations of the axonal transport rate in the triple transgenic mouse olfactory system, using fast multi-sliced T(1) mapping with manganese-enhanced MRI. The data show that impairment in axonal transport is a very early event in AD pathology in these mice, preceding both deposition of Aβ plaques and formation of Tau fibrils.     

In vivo axonal transport rates decrease in a mouse model of Alzheimer's disease

Axonopathy is a pronounced attribute of many neurodegenerative diseases. In Alzheimer's disease (AD), axonal swellings and degeneration are prevalent and may contribute to the symptoms of AD senile dementia. Current limitations in identifying the contribution of axonal damage to AD include the inability to detect when this damage occurs in relation to other identifiers of AD because of the invasiveness of existing methods. To overcome this, we further developed the MRI methodology Manganese Enhanced MRI (MEMRI) to assess in vivo axonal transport rates. Prior to amyloid-beta (Abeta) deposition, the axonal transport rates in the Tg2576 mouse model of AD were normal. As Abeta levels increased and before plaque formation, we observed a significant decrease in axonal transport rates of the Tg2576 mice compared to controls. After plaque formation, the decline in the transport rate in the Tg2576 mice became even more pronounced. These data indicate that in vivo axonal transport rates decrease prior to plaque formation in the Tg2576 mouse model of AD.     

Using Reiki to decrease memory and behavior problems in mild cognitive impairment and mild Alzheimer's disease

OBJECTIVES: This empirical study explored the efficacy of using Reiki treatment to improve memory and behavior deficiencies in patients with mild cognitive impairment or mild Alzheimer's disease. Reiki is an ancient hands-on healing technique reputedly developed in Tibet 2500 years ago. DESIGN: This study was a quasi-experimental study comparing pre- and post-test scores of the Annotated Mini-Mental State Examination (AMMSE) and Revised Memory and Behavior Problems Checklist (RMBPC) after four weekly treatments of Reiki to a control group. SETTINGS/LOCATION: The participants were treated at a facility provided by the Pleasant Point Health Center on the Passamaquoddy Indian Reservation. SUBJECTS: The sample included 24 participants scoring between 20 and 24 on the AMMSE. Demographic characteristics of the sample included an age range from 60 to 80, with 67% female, 46% American Indian, and the remainder white. INTERVENTIONS: Twelve participants were exposed to 4 weeks of weekly treatments of Reiki from two Reiki Master-level practitioners; 12 participants served as controls and received no treatment. OUTCOME MEASURES: The two groups were compared on pre- and post-treatment scores on the AMMSE and the Revised Memory and Behavior Problems Checklist (RMBPC). RESULTS: Results indicated statistically significant increases in mental functioning (as demonstrated by improved scores of the AMMSE) and memory and behavior problems (as measured by the RMBPC) after Reiki treatment. This research adds to a very sparse database from empirical studies on Reiki results. CONCLUSION: The results indicate that Reiki treatments show promise for improving certain behavior and memory problems in patients with mild cognitive impairment or mild Alzheimer's disease. Caregivers can administer Reiki at little or no cost, resulting in significant societal value by potentially reducing the needs for medication and hospitalization.     

APP/PS1阿尔茨海默病转基因动物模型前联合异常改变

背景:阿尔茨海默病研究大多主要集中在淀粉样β蛋白和神经元死亡之间的关系,但是对白质损害研究却鲜有报道.目的:观察APP/PS1阿尔茨海默病转基因动物模型前联合病理改变特点.设计、时间及地点:以组织学改变为依据,分组对照观察,于2007-09/2008-09在华中科技大学同济医学院附属同济医院神经科实验室完成.材料:雌性转基因APP/PS1小鼠(表达人突变的PS1(M1146L)基因和APP(KM670/671NL,V7171)基因,对照组老鼠选用的是没有淀粉样蛋白沉积的雌性PS1小鼠.分为年轻组(2月龄,包括8只APP/PS1,7只PS1)和老年组(24月龄,包括6只APP/PS1,7只PS1).方法:利用刚果红和免疫组织化学方法观测该AD转基因模型脑内淀粉样改变;采用氯化金髓鞘染色方法和轴突免疫组织化学染色,利用吸光度方法对前联合轴突密度和髓鞘化程度的染色进行相对吸光度定量分析.主要观察指标:①细胞内和细胞外淀粉样β蛋白的染色.②在冠状位前联合的平均面积大小测量.③前联合处轴突密度和髓鞘化程度定量相对吸光度值.结果:在老年组APP/PS1小鼠,大量的刚果红阳性染色出现在皮质,海马以及丘脑,前联合也出现阳性染色;细胞内淀粉样β蛋白仅出现在年轻组APP/PS1的皮质结构中.在老年组PS1组小鼠,前联合的表面积大小比年轻组PS1和老年组APP/PS1组小鼠都有显著的增长.老年组包括APP/PS1和PS1组轴突的染色都有显著的下降,髓鞘化程度比年轻组有增高趋势.不同表型分析显示,轴突密度和髓鞘化程度在年轻组APP/PS1和PS1组相当;老年APP/PS1组轴突密度比PS1组有显著的下降,老年组APP/PS1小鼠髓鞘化程度与PS1无显著差别.结论:随着年龄的增长,APP/PS1阿尔茨海默病转基因小鼠模型前联合存在着轴突的丢失,髓鞘相对保持完整.淀粉样β蛋白对轴突有直接的毒性作用.