BDNF和神经干细胞联用对穹隆海马伞切割鼠基底前脑p75NGFR阳性神经元数及其形态学的影响

目的研究神经干细胞（NSC）和脑源性神经营养因子（BDNF）联合治疗对穹隆海马伞切割鼠基底前脑p75^NGFR阳性神经元厦其形态学的影响。方法切断SD大鼠左侧穹隆海马伞模拟AD大鼠模型,利用无血清培养技术获得新生SD鼠的海马NSC。基底前脑注射NSC,同时侧脑室注射BDNF,4周后行免疫组化结合图象分析技术观察各组大鼠基底前脑p75^NGFR阳性神经元厦其形态学变化。结果损伤组大鼠p75^NGFR阳性神经元数在内侧隔核（MS）和斜角带（VDB）较正常组明显下降（P〈0．01）;移植组细胞数较损伤组有改善（P〈0．05）;与正常组相比较,联合组免疫阳性神经元数无显著下降（P〉0．05）。形态学参数测试结果显示,p75^NGFR阳性神经元的面积、周长在4组中的改变类似p75^NGFR阳性神经元数。结论NSC和BDNF联用较单独使用BDNF或NSC更好地增加p75^NGFR阳性神经元数及其形态学参数。     

神经干细胞移植对老年痴呆模型鼠基底前脑小白蛋白阳性神经元和 学习记忆能力的影响*☆

目的：基底前脑是老年性痴呆患者脑皮质下神经元丢失最严重的区域，实验拟验证经神经干细胞移植治疗后老年痴呆鼠基底前脑小白蛋白阳性神经元的变化以及对其空间学习记忆能力方面的影响。 方法：实验于2005-12/2006-07在广州医学院解剖学教研室完成。①动物：清洁级SD雄性大鼠28只，随机数字表法分为3组：正常对照组8只、模型对照组8只、细胞移植组12只。另取10只新生SD鼠用于神经干细胞的分离培养。实验过程中对动物的处置符合动物伦理学标准。②实验方法：模型对照组、细胞移植组大鼠切断左侧穹隆海马伞，建立老年性痴呆动物模型。利用无血清培养技术获得鼠基底前脑神经干细胞，吸取2.5×1010 L－1细胞悬液4 μL，术后即刻细胞移植组损伤侧行细胞移植，坐标为前囟+0.6 mm，外侧+0.6 mm插入，腹侧-5.5 mm。③实验评估：移植后4周，采用Y型迷宫对各组动物进行学习记忆能力检测。麻醉后取脑制备组织切片，ABC法免疫组化染色结合图像分析观察各组大鼠基底前脑小白蛋白阳性神经元的变化。 结果：①对空间学习记忆能力的影响：细胞移植组空间学习能力、记忆能力均显著高于模型对照组（P < 0.05或P < 0.01），基本达到正常水平（P > 0.05）。②对小白蛋白阳性神经元的影响：与正常对照组比较，模型对照组损伤侧内侧隔核和斜角带核的小白蛋白阳性神经元数目分别减少62.5%和30.4%；细胞移植组降低幅度明显小于模型对照组（P < 0.01）。与正常对照组比较，模型对照组损伤侧内侧隔核、斜角带核小白蛋白阳性神经元的面积、周长、灰度均显著降低（P < 0.05或0.01）；细胞移植组上述指标较模型对照组均显著增加（P < 0.05或0.01）。③相关性分析：小白蛋白阳性神经元数目与大鼠在Y型迷宫中的学习次数呈显著负相关（r =-0.76~-0.79，P < 0.01），与记忆能力呈显著正相关（r = 0.78~0.84，P < 0.01）。 结论：神经干细胞移植对老年性痴呆模型鼠基底前脑退变的小白蛋白阳性神经元具有补充和保护作用，并能够明显改善其学习记忆能力，二者呈正性相关。     

神经干细胞移植对AD鼠基底前脑NOS阳性神经元的影响

目的 探讨神经干细胞（neural stem cells,NSCs）移植对老年性痴呆鼠基底前脑一氧化氮合酶（NOS）阳性神经元的影响.方法 切断成年SD大鼠左侧穹窿海马伞（fimbria-fornix,FF）,于基底前脑行神经干细胞移植,4周后行组织化学染色结合图像分析技术观察各组大鼠基底前脑NOS阳性神经元数量和形态学参数的变化. 结果 损伤后大约1个月,损伤侧基底前脑内侧隔核（MS）和斜角带垂直支（VDB）内可观察到NOS阳性神经元明显减少,分别为正常组的35.5%和55.8%,（与正常组相比P＜0.01）;移植组NOS阳性神经元数恢复到正常组的74.7%和95.7%,（与损伤组相比P＜0.01）.细胞形态学参数提示移植组NOS阳性神经元中含部分中等大小的未成熟细胞.结论 神经干细胞移植治疗,对AD模型鼠基底前脑MS、VDB的NOS阳性神经元有明显的补充和保护作用。     

神经生长因子缓释微球植入后阿尔茨海默病模型鼠基底前脑神经生长因子受体阳性神经元的变化

背景：已有研究表明,神经营养因子对中枢和周围神经损伤后的存活修复有促进作用。然而,神经生长因子是大分子蛋白类物质,生物半衰期很短,很难透过血脑屏障,寻找有效的神经营养因子投递系统至关重要。 目的：观察了神经生长因子微球对阿尔茨海默病模型鼠基底前脑神经生长因子受体阳性神经元的保护作用。 设计、时间及地点：随机对照动物实验,于2005-11/2006-07在广州医学院神经生物学实验室完成。 材料：采用双乳化技术制备神经生长因子缓释微球。28只SD大鼠,随机分为3组：正常对照组8只,模型对照组8只,神经生长因子缓释微球植入组12只。 方法：模型对照组和神经生长因子缓释微球植入组左侧穹隆海马伞切断制备阿尔茨海默病模型,正常对照组不做任何处理。神经生长因子缓释微球植入组切断后即刻行基底前脑注射神经生长因子缓释微球。正常对照组和模型对照组注射等量生理盐水。 主要观察指标：注射4周后,利用免疫组化法观察各组大鼠基底前脑神经生长因子受体阳性神经元变化。 结果：28只大鼠均进入结果分析。模型对照组损伤侧的内侧隔核和斜角带核的神经生长因子受体阳性神经元大量减少,分别减少59.7%和54.4%;神经生长因子缓释微球植入组损伤侧的内侧隔核和斜角带核细胞数分别减少17.9%和19.8%,明显高于模型对照组损伤侧的神经生长因子受体阳性神经元存活数（P < 0.05）。 结论：神经生长因子缓释微球植入对阿尔茨海默病模型鼠基底前脑神经生长因子受体阳性神经元有明显的保护作用。     

脑源性神经营养因子修饰的神经干细胞移植对阿尔茨海默病大鼠的学习及p75表达的影响

目的研究脑源性神经营养因子(BDNF)修饰的神经干细胞(NSC)移植对阿尔茨海默病大鼠的学习及p75表达的影响。方法 36只SD成年大鼠被选为受试对象。采用Aβ1-40立体定向注射法制作阿尔茨海默病模型(AD),并将AD模型大鼠随机分为3组:BDNF修饰的神经干细胞(BDNF-NSC)移植组、神经干细胞移(NSC)植组和溶剂(Vehicle)对照组(n=6),然后分别向这3组大鼠的海马区注入500μl的BDNF-NSC悬液(5×105)、NSC悬液(5×105)和相同剂量的不含细胞的培养基。注射4w后,采用Y迷宫方法检测AD大鼠的空间学习和记忆能力,随之用过量麻醉的方法处死受试大鼠,立即取脑并分别采用免疫组织化学方法检测BDNF-NSC在海马区的表达和Western blot法检测p75蛋白在海马区的表达。结果 BDNF-NSC组大鼠的行为学能力较NSC组和Vehi-cle组明显提高(P<0.05),同时免疫组化检测显示在海马区的BDNF-NSC阳性细胞数明显增多而Western blot检测显示p75蛋白在该区的表达显著降低(P<0.05)。结论 BDNF修饰的神经干细胞能够通过抑制海马区p75表达来防止由Aβ1-40造成的神经损害。     

神经干细胞植入阿尔茨海默病鼠脑后的效果观察

神经干细胞移植治疗阿尔茨海默病鼠包括细胞替代治疗和基因治疗,神经干细胞移植阿尔茨海默病鼠脑后其组织形态学与行为学效应均可以得到不同程度的修复和改善。细胞替代治疗中,神经干细胞与神经营养因子联合移植效应优于单纯的神经干细胞移植,但目前对神经干细胞体内分化机制的不确定导致了神经干细胞移植治疗的盲目性,同时对影响其疗效的各种可能因素也缺乏比较研究。神经干细胞基因治疗具有细胞替代和基因治疗的双重作用,但尚处于研究的初期阶段,仍以NGF,BDNF,GDNF等单一营养因子基因修饰的神经干细胞移植治疗为主,且转基因神经干细胞移植入阿尔茨海默病鼠脑后外源基因表达效率、促分化、功能修复情况以及安全性的研究还很缺乏。目前神经干细胞移植治疗阿尔茨海默病鼠脑后的疗效检测技术手段比较单一,免疫组化方法与活体示踪技术的结合、形态学指标与功能学指标的综合检测是疗效检测的发展趋势。     

神经干细胞移植对阿尔茨海默病大鼠海马突触素表达和学习记忆能力的影响*

背景：前期实验已证实,移植入阿尔茨海默病大鼠脑内的神经干细胞能够存活、增殖,但其是否可替代损伤或坏死的神经细胞而重建神经通路,改善学习记忆能力尚不清楚。突触素是突触重建的重要标记之一。 目的：观察神经干细胞移植对阿尔茨海默病大鼠学习记忆能力及突触表达的影响。 方法：SD大鼠随机数字表法分为正常对照组、阿尔茨海默病模型组、2周移植组和4周移植组,除正常对照组外制备阿尔茨海默病模型。另取新生24 h SD大鼠海马齿状回分离、培养神经干细胞,经Hoechst33258标记后植入2周和4周移植组海马CA1区,行Y迷宫实验检测大鼠的学习记忆能力,然后取脑进行尼氏染色和突触素免疫组织化学染色。阿尔茨海默病模型组则以同样的方法、同样的位点注入等量无菌生理盐水。正常对照组不施以任何处理。 结果与结论：①2周和4周移植组海马CA1区细胞比阿尔茨海默病模型组增多,但仍少于正常对照组(P < 0.05),平均吸光度与正常对照组相比差异无显著性意义(P > 0.05)。②2周移植组和4周移植组大鼠海马结构内突触素吸光度值明显高于正常对照组和阿尔茨海默病模型组(P < 0.05)。③与阿尔茨海默病模型组相比,2周和4周移植组大鼠学习能力和记忆能力均显著增强,正确反应率明显提高(P < 0.05),而与正常对照组相比,差异无显著性意义(P > 0.05)。提示移植入脑内的神经干细胞可促进突触形成,改善学习记忆能力。     

阿尔茨海默病海马CA1区p75NTR和磷酸化tau蛋白神经元的定量观察

目的观察阿尔茨海默病(AD)海马CA1区p5NTR的表达与磷酸化tau蛋白的关系.方法利用组织化学和免疫细胞化学方法分析由荷兰脑库提供的10例女性AD患者及年龄、性别等与之匹配的10例健康意外死亡对照者的脑组织标本海马CA1区神经元总数、p75NTR神经元数目的差异及AD患者p75NTR和Alz-50共存.结果AD患者海马CA1区神经元总数明显低于对照组,但p75NTR神经元占总神经元的百分比明显高于对照组(P值分别为0.0002、0.001);AD海马CA1区Alz-50阳性神经元(个/mm2)为87.5±29.2,p75NTR和Alz-50双标神经元为76.4±26.6,后者占前者的百分比为86.6%±5.0%,二者在CA1区的分布呈正相关(r=0.79、P=0.006).结论AD患者海马CA1区p75NTR主要产生死亡信号,参与AD神经病理的形成.     

白藜芦醇对神经干细胞诱导分化为多巴胺能神经元移植治疗帕金森模型鼠的影响

背景：目前神经干细胞体外诱导分化的多巴胺能神经元移植治疗帕金森病仍面临细胞存活率低的问题,大部分细胞因氧自由基形成及脂质过氧化而发生程序性凋亡。 目的：探讨白藜芦醇对神经干细胞体外诱导分化的多巴胺能神经元移植至帕金森模型鼠后的细胞存活及移植效果的影响。 设计、时间及地点：随机对照动物实验,于2007-10/2008-06在中山大学动物实验中心完成。 材料：成年健康雄性SD大鼠32只,随机分为模型对照组、多巴胺能神经元组、白藜芦醇组、联合组,8只/组;孕十四五天的健康SD大鼠4只,取胎鼠用于神经干细胞的分离培养。白藜芦醇为深圳晶美生物工程有限公司产品。 方法：取体外分离培养的胎鼠中脑神经干细胞,在含表皮生长因子、碱性成纤维细胞生长因子的无血清培养液中传代扩增后,在分化液中诱导向多巴胺能神经元方向分化。各组大鼠均应用6-羟基多巴胺制备帕金森病模型。采用两点移植法,多巴胺能神经元组向大鼠毁损同侧纹状体注入多巴胺能神经元细胞悬液3 μL (1×105个/μL);白藜芦醇组注入40 mg/L白藜芦醇3 μL;联合组注入40 mg/L白藜芦醇3 μL+多巴胺能神经元细胞悬液3 μL (1×105个/μL);模型对照组注入DMEM/F12细胞培养液3 μL。 主要观察指标：胎鼠神经干细胞诱导分化的酪氨酸羟化酶染色阳性细胞率,细胞移植后帕金森模型鼠不对称旋转行为的变化,纹状体移植区酪氨酸羟化酶染色阳性细胞存活情况。 结果：流式细胞仪检测诱导分化6 d的细胞中酪氨酸羟化酶染色阳性细胞率为(17.8±4.2)%。与模型对照组比较,联合组大鼠移植后10 d不对称旋转行为有显著性改善(P < 0.01),移植后20 d不对称旋转圈数开始明显下降(P < 0.01)。移植后10~ 60 d,联合组大鼠的不对称旋转圈数明显低于多巴胺能神经元组(P < 0.01)。白藜芦醇组、模型对照组均未见酪氨酸羟化酶染色阳性细胞,联合组酪氨酸羟化酶染色阳性细胞数明显多于多巴胺能神经元组(P < 0.01)。 结论：胎鼠神经干细胞诱导分化的多巴胺能神经元移植至帕金森模型鼠后,白藜芦醇可提高纹状体移植区植入细胞的存活率,改善大鼠不对称旋转行为。     

侧脑室注射p75~(NTR-ECD)对AD小鼠海马DCX表达与认知功能的影响

目的研究侧脑室注射p75NTR胞外段(extracellular domain of p75NTR,p75NTR-ECD)阻断内源性p75NTR对阿尔茨海默病(Alzheimer's disease,AD)小鼠海马神经发生和认知功能的影响。方法选取12月龄APP/PS1双转基因AD小鼠,实验组连续7d侧脑室注射p75NTR-ECD(1μg/d),对照组向侧脑室注射等量生理盐水,空白对照组未予处置,Morris水迷宫检测其认知功能,免疫组化检测海马齿回Doublecortin(DCX)的表达变化。结果与生理盐水对照组及空白对照组相比,侧脑室注射p75NTR-ECD组小鼠海马齿回DCX阳性细胞数显著增加(P0.01),行为学检测显示逃逸潜伏期缩短、穿过原平台位置次数和在原平台象限探索时间百分率增加(P0.05),生理盐水注射组和空白对照组DCX阳性细胞数及行为学检测显示差异无统计学意义(P0.05)。结论 p75NTR-ECD可促进AD小鼠海马神经发生并改善AD小鼠认知功能。     

Co-expression of p75- and calbindin-immunoreactivity in cholinergic neurons of the raccoon basal forebrain

The cholinergic system of the basal forebrain is involved in the modulation of sensory information. This has previously been investigated in the raccoon, an animal especially interesting because of its highly developed somatosensory cortex. The present study focused on the co-expression of the low-affinity neurotrophin receptor p75^NTR and calbindin in cholinergic neurons of the raccoon basal forebrain and neostriatum. Carbocyanine immunofluorescence double labelling revealed the co-localization of choline acetyltransferase and p75^NTR as well as calbindin in a large portion of basal forebrain neurons, but not in the neostriatum. In contrast, immunolabelling of two other calcium-binding proteins, parvalbumin and calretinin, was found exclusively in non-cholinergic neurons.     

Neurofibrillary degeneration of cholinergic and noncholinergic neurons of the basal forebrain in Alzheimer's disease

Two principal features of Alzheimer's disease (AD) are (1) the occurrence of neurofibrillary tangles (NFTs) and senile plaques, and (2) the loss of cortical cholinergic activity because of dysfunction of neurons in the basal forebrain cholinergic system. The relationship of these two abnormalities is an unresolved issue in the pathology of AD. We used polyclonal antibodies specific for paired helical filaments (PHFs), combined with acetylcholinesterase (AChE) histochemistry, to assess the cytoskeletal changes of cholinergic and noncholinergic neurons in the basal forebrain in AD. In both sporadic and familial AD, the nucleus basalis of Meynert (nbM) showed a marked decrease in AChE-positive (AChE+) perikarya and abundant immunoreactive NFTs. In double-labeling studies of the nbM, PHF reactivity was found both in surviving AChE+ neurons and in many AChE- NFTs that were not associated with microscopically recognizable cell structures. Some surviving AChE+ perikarya did not contain NFTs. Numerous NFTs and senile plaques were identified by PHF immunoreactivity in other basal forebrain areas, including subnuclei of the amygdala that showed low or absent AChE activity. We conclude that the dysfunction and death of cholinergic neurons in the nbM is associated with extensive NFT formation, including apparently residual NFTs in loci where nbM neurons once existed; and many noncholinergic neurons and neurites in the basal forebrain show NFT and senile plaque formation. The cytopathology of AD involves neurons of varying transmitter specificities, including cholinergic neurons in the basal forebrain.     

Selective in vivo fluorescence labelling of cholinergic neurons containing p75 in the rat basal forebrain

The cholinergic system of the rat basal forebrain is used as a model for the homologous region in humans which is highly susceptible to neuropathological alterations as in Alzheimer's disease. Cholinergic cells in the basal forebrain express the low-affinity neurotrophin receptor p75^NTR. This has been utilized for selective immunolesioning of cholinergic neurons after internalization of an immunotoxin composed of anti-p75^NTR and the ribosome-inactivating toxin saporin. However, the goal of many studies may be not the lesion, but the identification of cholinergic cells after other experimentally induced alterations in the basal forebrain. Therefore, a novel cholinergic marker was prepared by conjugating the monoclonal antibody 192IgG directed against p75^NTR with the bright red fluorochrome carbocyanine 3 (Cy3). Three days after intraventricular injection of Cy3-192IgG the fluorescence microscopic analysis revealed a pattern of Cy3-labelled cells matching the distribution of cholinergic neurons. Apparently the marker was internalized within complexes of p75^NTR and Cy3-192IgG which were then retrogradely transported to the cholinergic perikarya of the basal forebrain. In addition to the even labelling of somata, a strong punctate-like Cy3-immunofluorescence was seen in structures resembling lysosomes. The specificity of the in vivo staining was proven by subsequent immunolabelling of choline acetyltransferase (ChAT) with green fluorescent Cy2-tagged secondary antibodies. In the medial septum, the diagonal band and the nucleus basalis only cholinergic neurons were marked by Cy3-192IgG. In parallel experiments, digoxigenylated 192IgG was not detectable within cholinergic basal forebrain neurons after intraventricular injection. Presumably, this modified antibody could not be internalized. On the other hand, digoxigenylated 192IgG was found to be an excellent immunocytochemical marker for p75^NTR as shown by double labelling including highly sensitive mouse antibodies directed against ChAT. Based on the present findings, future applications of the apparently non-toxic Cy3-192IgG and other antibodies for fluorescent in vivo and in vitro labelling are discussed.     

Heterogeneity and selectivity of the degeneration of cholinergic neurons in the basal forebrain of patients with Alzheimer's disease

Cholinergic neurons were studied by immunohistochemistry, with an antiserum against choline acetyltransferase (ChAT), in the basal forebrain (Ch1 to Ch4) of four patients with Alzheimer's disease (AD) and four control subjects. ChAT-positive cell bodies were mapped and counted in Ch1 (medial septal nucleus), Ch2 (vertical nucleus of the diagonal band), Ch3 (horizontal nucleus of the diagonal band) and Ch4 (nucleus basalis of Meynert). Compared to controls, the number of cholinergic neurons in AD patients was reduced by 50% on average. The interindividual variations in cholinergic cell loss were high, neuronal loss ranging from moderate (27%) to severe (63%). Despite the small number of brains studied, a significant correlation was found between the cholinergic cell loss and the degree of intellectual impairment. To determine the selectivity of cholinergic neuronal loss in the basal forebrain of AD patients, NPY-immunoreactive neurons were also investigated. The number of NPY-positive cell bodies was the same in controls and AD patients. The results (1) confirm cholinergic neuron degeneration in the basal forebrain in AD and the relative sparing of these neurons in some patients, (2) indicate that degneration of cholinergic neurons in the basal forebrain contributes to intellectual decline, and (3) show that, in AD, such cholinergic cell loss is selective, since NPY-positive neurons are preserved in the basal forebrain.     

Derivation of neural stem cells from an animal model of psychiatric disease

Several psychiatric and neurological diseases are associated with altered hippocampal neurogenesis, suggesting differing neural stem cell (NSC) function may play a critical role in these diseases. To investigate the role of resident NSCs in a murine model of psychiatric disease, we sought to isolate and characterize NSCs from alpha-calcium-/calmodulin-dependent protein kinase II heterozygous knockout (CaMK2α-hKO) mice, a model of schizophrenia/bipolar disorder. These mice display altered neurogenesis, impaired neuronal development and are part of a larger family possessing phenotypic and behavioral correlates of schizophrenia/bipolar disorder and a shared pathology referred to as the immature dentate gyrus (iDG). The extent to which NSCs contribute to iDG pathophysiology remains unclear. To address this, we established heterogeneous cultures of NSCs isolated from the hippocampal neuropoietic niche. When induced to differentiate, CaMK2α-hKO-derived NSCs recapitulate organotypic hippocampal neurogenesis, but generate larger numbers of immature neurons than wild-type (WT) littermates. Furthermore, mutant neurons fail to assume mature phenotypes (including morphology and MAP2/calbindin expression) at the same rate observed in WT counterparts. The increased production of immature neurons which fail to mature indicates that this reductionist model retains key animal- and iDG-specific maturational deficits observed in animal models and human patients. This is doubly significant, as these stem cells lack several developmental inputs present in vivo. Interestingly, NSCs were isolated from animals prior to the emergence of overt iDG pathophysiology, suggesting mutant NSCs may possess lasting intrinsic alterations and that altered NSC function may contribute to iDG pathophysiology in adult animals.     

Hibernation model of tau phosphorylation in hamsters: selective vulnerability of cholinergic basal forebrain neurons - implications for Alzheimer's disease

Neurofibrillar tangles made up of 'paired helical filaments' (PHFs) consisting of hyperphosphorylated microtubule-associated protein tau are major hallmarks of Alzheimer's disease (AD). Tangle formation selectively affects certain neuronal types and systematically progresses throughout numerous brain areas, which reflects a hierarchy of neuronal vulnerability and provides the basis for the neuropathological staging of disease severity. Mechanisms underlying this selective neuronal vulnerability are unknown. We showed previously that reversible PHF-like phosphorylation of tau occurs during obligate hibernation. Here we extend these findings to facultative hibernators such as Syrian hamsters (Mesocricetus auratus) forced into hibernation. In this model, we showed in the basal forebrain projection system that cholinergic neurons are selectively affected by PHF-like phosphorylated tau, while gamma-aminobutyric acid (GABA)ergic neurons are largely spared, which shows strong parallels to the situation in AD. Formation of PHF-tau in these neurons apparently does not affect their function as pacemaker for terminating hibernation. We conclude that although formation of PHF-like phosphorylated tau in the mammalian brain follows a certain hierarchy, affecting some neurons more frequently than others, it is not necessarily associated with impaired neuronal function and viability. This indicates a more general link between PHF-like phosphorylation of tau and the adaptation of neurons under conditions of a 'vita minima'.     

Morphometric study of the magnocellular basal forebrain system in patients with Alzheimer's disease

Morphometric study of neurons within the magnocellular basal forebrain system (MBFS) in the three normal controls and three cases with Alzheimer's disease (AD) was studied. Immunocytochemical staining using anti-acetylcholinesterase was performed to identify the measuring areas of the MBFS, and cross sectional areas of all neurons within the MBFS in one preparation was measured making use of cresyl violet staining. About 50% of the entire neuronal cells within the MBFS were decreased and case 2 had neurofibrillary tangles in the substantia innominata. In the septal nucleus neuronal cell depopulation was observed through the all range of the neuronal cell size, and in the diagonal band of Broca neuronal cells of which cross sectional areas were more than 200 microns2 were preferentially decreased and case 3 had inverse increase of the neurons of which cross sectional areas were less than 200 microns2. In the basal nucleus of Meynert in the substantia innominata neurons of which cross sectional areas were more than 250 microns2 were markedly decreased and neurons of which cross sectional areas less than 250 microns2 were well preserved. The large neurons within the basal nucleus and diagonal band of Broca were more affected in AD. In the septal nucleus and diagonal band it was suspected that non-cholinergic neurons were also decreased and these findings suggested that other series of monoamines also bore a relationship to the dementia and neuropsychological symptoms in AD.     

Loss of basal forebrain P75(NTR) immunoreactivity in subjects with mild cognitive impairment and Alzheimer's disease.

The long-held belief that degeneration of the cholinergic basal forebrain was central to Alzheimer's disease (AD) pathogenesis and occurred early in the disease process has been questioned recently. In this regard, changes in some cholinergic basal forebrain (CBF) markers (e.g. the high affinity trkA receptor) but not others (e.g., cortical choline acetyltransferase [ChAT] activity, the number of ChAT and vesicular acetylcholine transporter-immunoreactive neurons) suggest specific phenotypic changes, but not frank neuronal degeneration, early in the disease process. The present study examined the expression of the low affinity p75 neurotrophin receptor (p75(NTR)), an excellent marker of CBF neurons, in postmortem tissue derived from clinically well-characterized individuals who have been classified as having no cognitive impairment (NCI), mild cognitive impairment (MCI), and mild AD. Relative to NCI individuals, a significant and similar reduction in the number of nucleus basalis p75(NTR)-immunoreactive neurons was seen in individuals with MCI (38%) and mild AD (43%). The number of p75(NTR)-immunoreactive nucleus basalis neurons was significantly correlated with performance on the Mini-Mental State Exam, a Global Cognitive Test score, as well as some individual tests of working memory and attention. These data, together with previous reports, support the concept that phenotypic changes, but not frank neuronal degeneration, occur early in cognitive decline. Although there was no difference in p75(NTR) CBF cell reduction between MCI and AD, it remains to be determined whether these findings lend support to the hypothesis that MCI is a prodromal stage of AD.