Molecular basis of Alzheimer's disease: From amyloid hypothesis to treatment in the foreseeable future

Alzheimer's disease (AD) is the most common dementing disorder in the elderly. It is clinically characterized by insidious onset of memory disturbance followed by slowly progressive global dementia. The patient's brain at autopsy shows diffuse cerebral atrophy, and microscopic findings are characterized by the presence of intraneuronal neurofibrillary tangle (NFT), senile plaques with extraneuronal β amyloid deposits, and dystrophic changes of neuronal processes with synaptic and neuronal loss. The pathological mechanism of these hallmarks are now well understood on the molecular basis, and new strategies to prevent and reverse these pathological changes are now being developed. Here I review some personal interest of the mechanism, and describe future strategies for prevention and treatment of AD.     

Inhibition of platelet activation by the Alzheimer's disease amyloid precursor protein

The amyloid precursor protein (APP) of Alzheimer's disease is abundantly expressed in the platelet α-granule where its role remains unclear. This study describes a novel function for APP in regulating human platelet activation. Preincubation of platelet-rich plasma with recombinant secreted APP (sAPP) isoforms dose-dependently inhibited platelet aggregation and secretion induced by ADP or adrenaline. Similarly, sAPP potently inhibited low-dose thrombin-induced activation in washed platelet suspensions, indicating that the activity does not require plasma cofactors. There were no functional differences between sAPP forms with or without the Kunitz protease inhibitor domain or derived from either α- or β-secretase cleavage. In fact, the N-terminal cysteine-rich region of APP (residues 18–194) was as effective as the entire sAPP region in the inhibition of platelet activation. The inhibitory activity of sAPP correlated with a significant reduction in the agonist-induced production of the arachidonic acid (AA) metabolites thromboxane B₂ and prostaglandin E₂. However, sAPP did not affect AA-induced platelet aggregation or secretion, indicating the enzymatic conversion of AA was not inhibited. The addition of a threshold dose of AA reversed the sAPP-inhibition of agonist-induced platelet activation. This suggests that sAPP decreases the availability of free AA, although the mechanism is not yet known. These data provide evidence that the release of sAPP upon platelet degranulation may result in negative feedback regulation during platelet activation.     

Transgenic mice expressing Alzheimer amyloid precursor proteins

—Nearly a decade after the identification of the Alzheimer amyloid precursor protein (APP) gene several groups of investigators have created transgenic mice expressing APP that simulate some of the prominent behavioral and pathological features of Alzheimer’s disease Quon et al 1991, Games et al 1995, Hsiao et al 1995, Hsiao et al 1996, Moechars et al 1996 and Sturchler-Pierrat et al 1997. These features, which are present to various degrees in different lines of mice, include age-related impairment in learning and memory, neuronal loss, gliosis, neuritic changes, amyloid deposition, and abnormal tau phosphorylation. No mouse model exhibiting every neuropathological feature of Alzheimer’s disease exists. Whether an exact simulation of Alzheimer neuropathology is required to understand neural dysfunction in Alzheimer’s disease is unclear. Various mouse models of Alzheimer’s disease are summarized in this article.     

APP转基因小鼠与正常小鼠脑蛋白质组双向电泳图谱的比较

目的探讨APP转基因小鼠与正常C57小鼠脑蛋白质组双向电泳(2-DE)图谱差异,从蛋白质水平初步探索老年性痴呆发病机制。方法APP转基因小鼠与正常C57小鼠脑组织经蛋白提取后,分别以固相pH梯度等电聚焦为第一向,SDS-PAGE垂直电泳为第二向进行2-DE。图像分析软件ImageMaster 2D Elite分析电泳图谱。结果APP转基因小鼠与正常小鼠脑组织2-DE图谱分别检测出976和947个蛋白点。对两张电泳图进行匹配后,发现有16个蛋白点仅在APP转基因小鼠脑蛋白2-DE图谱检测到表达,而有7个蛋白点只在正常小鼠检测到。部分蛋白在2组小鼠脑组织中含量发生了明显变化。结论差异点的发现初步建立了差异表达蛋白质组学的技术方法;为研究阿尔茨海默病机制及研发新药提供了有益的线索。     

Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer's disease

The principal pathological features of Alzheimer's disease (AD) are extracellular amyloid plaques and intracellular neurofibrillary tangles, the latter composed of the microtubule-binding protein tau assembled into paired helical and straight filaments. Recent studies suggest that these pathological entities may be functionally linked, although the mechanisms by which amyloid deposition promotes pathological tau filament assembly are poorly understood. Here, we report that tau is proteolyzed by multiple caspases at a highly conserved aspartate residue (Asp421) in its C terminus in vitro and in neurons treated with amyloid-beta (Abeta) (1-42) peptide. Tau is rapidly cleaved at Asp421 in Abeta-treated neurons (within 2 h), and its proteolysis appears to precede the nuclear events of apoptosis. We also demonstrate that caspase cleavage of tau generates a truncated protein that lacks its C-terminal 20 amino acids and assembles more rapidly and more extensively into tau filaments in vitro than wild-type tau. Using a monoclonal antibody that specifically recognizes tau truncated at Asp421, we show that tau is proteolytically cleaved at this site in the fibrillar pathologies of AD brain. Taken together, our results suggest a novel mechanism linking amyloid deposition and neurofibrillary tangles in AD: Abeta peptides promote pathological tau filament assembly in neurons by triggering caspase cleavage of tau and generating a proteolytic product with enhanced polymerization kinetics.     

Alzheimer's disease: Mechanisms and development of therapeutic strategies

Senile plaques are the most characteristic change in Alzheimer's disease (AD). In senile plaques, β amyloid is deposited, which is composed of aggregated amyloid β protein (Aβ) derived from amyloid precursor protein (APP). Therefore, it is suggested that there exists a mechanism of increase of Aβ production or a decrease of Aβ degradation and/or clearance of β amyloid in AD. Mutations in familial Alzheimer's disease (FAD) genes such as APP , presenilin 1 ( PS1 ) and presenilin 2 ( PS2 ) result in an increase of Aβ production. Apolipoprotein E (ApoE), a genetic risk factor for AD, is involved in Aβ production and/or its clearance. Thus, it is suggested that an inhibition of Aβ production and a facilitation of β amyloid degradation and clearance delay the clinical onset and progression of AD, and it is possible to cure AD even after an onset of the disease, if it is still at an early phase. Researchers studied the fine mechanisms of Aβ production and identified enzymes that cleave-out Aβ from APP. Inhibitors of the cleaving enzymes are proven to be effective in ameliorating AD-like conditions in its animal models and are now being applied to humans. Researchers also found an efficient way of clearing β amyloid deposits using the immune system, which was effective in animal models. When it was applied to humans, some patients developed meningoencephalitis as a side-effect. Therefore, safer vaccines are now being developed. It did not require 20 years for researchers to develop therapeutic strategies since the discovery of Aβ in 1984. Now that AD is becoming a treatable disease, early diagnosis and early treatment will soon become the rule. Notably, AD may not be a psychiatric disorder any more, and mainly neurologists and geriatricians will see patients. Thus, neurogeriatrics will become more and more important.     

Melatonin alleviates behavioral deficits associated with apoptosis and cholinergic system dysfunction in the APP 695 transgenic mouse model of Alzheimer's disease

Melatonin is an endogenous antioxidant and free radical scavenger. A transgenic (Tg) mouse model for Alzheimer's disease mimics the accumulation of senile plaques, neuronal apoptosis and memory impairment. Previous studies indicated that melatonin reduced beta-amyloid (Abeta)-induced neurotoxicity. In this study, after giving melatonin at 10 mg/kg to APP 695 transgenic (APP 695 Tg) mice for 4 months, we evaluated the long-term influence of melatonin on behavior, biochemical and neuropathologic changes in APP 695 Tg mice. Step-down and step-through passive avoidance tests suggested that 8-month-old APP 695 Tg mice showed decreases in step-down latency and step-through latency and increases in count of error throughout the entire learning trial and memory session, which suggested learning and memory impairment. However, melatonin alleviated learning and memory deficits. Additionally, choline acetyltransferase (ChAT) activity also decreased in the frontal cortex and hippocampus of APP 695 Tg mice compared with non-Tg littermates. Melatonin supplementation increased ChAT activity in the frontal cortex and hippocampus. DNA fragmentation was present in the frontal cortex of the APP 695 Tg mice; melatonin reduced the number of apoptotic neurons. Congo Red staining and Bielschowsky silver impregnation both showed the apparent extracellular Abeta deposition in frontal cortex of APP 695 Tg mice. However, melatonin decreased the Abeta deposits. Our results indicate that neuroprotection by melatonin is partly related to modulation of apoptosis and protection of the cholinergic system. Early rational melatonin interventions may be one of the most promising strategies in the development of approaches to retard or prevent Abeta-mediated disease progression.     

APP/PS1双转基因小鼠阿尔茨海默病模型研究进展

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Oophorectomy promotes islet amyloid formation in a transgenic mouse model of Type II diabetes

Aims/hypothesis. In Type II (non-insulin-dependent) diabetes mellitus, amyloid depletes islet mass. We previously found that 81 % of male human islet amyloid polypeptide (IAPP) transgenic mice but only 11 % of female mice developed islet amyloid, suggesting that either testosterone promotes or ovarian products protect against amyloid deposition.¶Methods. We did a bilateral oophorectomy or sham procedure in female human IAPP transgenic mice (n = 11 and n = 8, respectively) and in female non-transgenic mice (n = 7 and n = 9, respectively) at 6–8 weeks of age. Animals were followed for 1 year on a 9 % fat (w/w) diet. Before we killed them we measured, fasting plasma human IAPP and did an intraperitoneal glucose tolerance test. Pancreatic content of IAPP and immunoreactive insulin (IRI) were estimated and pancreata were analysed for islet amyloid.¶Results. No amyloid was detected in either the sham-operated transgenic mice or, as expected, in both groups of non-transgenic mice. In strong contrast, 7 of 11 (64 %) oophorectomized mice developed islet amyloid (p < 0.05). Amyloid deposition in the oophorectomized transgenic mice was not associated with any differences in incremental body weight, fasting human IAPP concentrations or glucose tolerance between the groups. Furthermore, pancreatic content of mouse IAPP, human IAPP and immunoreactive insulin did not differ between groups.¶Conclusion/interpretation. Oophorectomy is associated with an enhancement of islet amyloid formation in the absence of changes in glucose tolerance, circulating IAPP or pancreatic content of IRI, mouse or human IAPP. Thus, the early stages of islet amyloidogenesis seem to be independent of glucose tolerance, with ovarian products having a protective role. [Diabetologia (2000) 43: 1309–1312]     

Binding and safety profile of novel benzoxazole derivative for in vivo imaging of amyloid deposits in Alzheimer's disease

Background:   In vivo detection of amyloid deposits in the brain is potentially useful for early diagnosis of Alzheimer's disease (AD) and tracking the efficacy of anti-amyloid therapy.
Methods:   To develop an amyloid-binding agent for positron emission tomography, we screened over 2600 compounds.
Results:   We found benzoxazole derivatives as candidate compounds for in vivo amyloid imaging probes. One of these agents, 2-(2-[2-dimethylaminothiazol-5-yl]ethenyl)-6-(2-[fluoro]ethoxy)benzoxazole (BF-227), displays high binding affinity to Aβ fibrils. BF-227 binding increased linearly with increasing Aβ fibril formation. In temporal and hippocampal AD brain sections, BF-227 selectively bound to amyloid plaques. In contrast, no staining was evident in the cerebellum. Compared with the previously reported compound BF-168, ¹⁸F-labeled BF-227 displayed selective in vivo labeling of amyloid fibrils and rapid washout from white matter areas in an Aβ-injected rat model. An acute and subacute toxicity study of BF-227 indicated sufficient safety for clinical use as a positron emission tomography probe.
Conclusions:   These findings suggest that BF-227 is feasible as an in vivo imaging probe of amyloid deposits in AD patients.     

Current status of metals as therapeutic targets in Alzheimer's disease

There is accumulating evidence that interactions between beta-amyloid and copper, iron, and zinc are associated with the pathophysiology of Alzheimer's disease (AD). A significant dyshomeostasis of copper, iron, and zinc has been detected, and the mismanagement of these metals induces beta-amyloid precipitation and neurotoxicity. Chelating agents offer a potential therapeutic solution to the neurotoxicity induced by copper and iron dyshomeostasis. Currently, the copper and zinc chelating agent clioquinol represents a potential therapeutic route that may not only inhibit beta-amyloid neurotoxicity, but may also reverse the accumulation of neocortical beta-amyloid. A Phase II double-blind clinical trial of clioquinol with B12 supplementation will be published soon, and the results are promising. This article summarizes the role of transition metals in amyloidgenesis and reviews the potential promise of chelation therapy as a treatment for AD.     

Unexpected functional consequences of xenogeneic transgene expression in β-cells of NOD mice

We describe unexpected alterations in the non-obese diabetic (NOD/Lt) mouse model of type 1 diabetes (T1D) following forced β-cell expression of non-mammalian genes ligated to an insulin promoter sequence. These include the jellyfish green fluorescent protein (GFP), useful for β-cell identification, and the bacteriophage P1 Cre recombinase, necessary for β cell–specific ablation of a gene using a Cre- loxP system. Homozygous expression of GFP, driven by the mouse insulin 1 gene promoter (MIP-GFP) in a single transgenic line of NOD mice, produced T1D in postnatal mice that was not associated with insulitis, but rather β cell–depleted islets. Hemizygous transgene expression suppressed spontaneous autoimmune T1D in females, and produced a male glucose intolerance syndrome associated with age-dependent declines in plasma insulin content. Among lines of transgenic NOD/Lt mice expressing Cre recombinase driven by the rat insulin 2 promoter (RIP-Cre), high, non-mosaic expression correlated with suppressed T1D development. These findings emphasize the need for careful characterization of genetically manipulated NOD mouse stocks to insure that model characteristics have not been compromised.     

Serum amyloid A in Alzheimer's disease brain is predominantly localized to myelin sheaths and axonal membrane

Immunohistochemical localization of the injury specific apolipoprotein, acute phase serum amyloid A (A-apoSAA), was compared in brains of patients with neuropathologically confirmed Alzheimer's disease (AD), multiple sclerosis (MS), Parkinson's disease (PD), Pick's disease (Pick's), dementia with Lewy bodies (DLB), coronary artery disease (CAD), and schizophrenia. Affected regions of both AD and MS brains showed intense staining for A-apoSAA in comparison to an unaffected region and non-AD/MS brains. The major site of A-apoSAA staining in both diseases was the myelin sheaths of axons in layers V and VI of affected cortex. A-apoSAA contains a cholesterol binding site near its amino terminus and is likely to have a high affinity for cholesterol-rich myelin. These findings, along with our recent evidence that A-apoSAA can inhibit lipid synthesis in vascular smooth muscle cells suggest that A-apoSAA plays a role in the neuronal loss and white matter damage occurring in AD and MS.     

Protection against cognitive deficits and markers of neurodegeneration by long-term oral administration of melatonin in a transgenic model of Alzheimer disease

Abstract: The neurohormone melatonin has been reported to exert anti-β-amyloid aggregation, antioxidant, and anti-inflammatory actions in various in vitro and animal models. To comprehensively determine the potential for long-term melatonin treatment to protect Alzheimer’s transgenic mice against cognitive impairment and development of β-amyloid (Aβ) neuropathology, we administered melatonin (100 mg/L drinking water) to APP + PS1 double transgenic (Tg) mice from 2–2.5 months of age to their killing at age 7.5 months. A comprehensive behavioral battery administered during the final 6 weeks of treatment revealed that Tg mice given melatonin were protected from cognitive impairment in a variety of tasks of working memory, spatial reference learning/memory, and basic mnemonic function; Tg control mice remained impaired in all of these cognitive tasks/domains. Immunoreactive Aβ deposition was significantly reduced in hippocampus (43%) and entorhinal cortex (37%) of melatonin-treated Tg mice. Although soluble and oligomeric forms of Aβ1-40 and 1-42 were unchanged in the hippocampus and cortex of the same melatonin-treated Tg mice, their plasma Aβ levels were elevated. These Aβ results, together with our concurrent demonstration that melatonin suppresses Aβ aggregation in brain homogenates, are consistent with a melatonin-facilitated removal of Aβ from the brain. Inflammatory cytokines such as tumor necrosis factor (TNF)-α were decreased in hippocampus (but not plasma) of Tg+ melatonin mice. Finally, the cortical mRNA expression of three antioxidant enzymes (SOD-1, glutathione peroxidase, and catalase) was significantly reduced to non-Tg levels by long-term melatonin treatment in Tg mice. Thus, melatonin’s cognitive benefits could involve its anti-Aβ aggregation, anti-inflammatory, and/or antioxidant properties. Our findings provide support for long-term melatonin therapy as a primary or complementary strategy for abating the progression of Alzheimer disease.     

Administration of β-glucan following Leishmania major infection suppresses disease progression in mice

Summary The potential of β-glucan (glucan) to suppress the progression of lesions caused by virulent strains of Leishmania major in genetically susceptible BALB/c mice when administered post challenge was evaluated. Glucan particles (glucan^p) prepared from Saccharomyces cerevisiae were injected i.v. at 7-day intervals starlins 7 days after parasite challenge. Four injections gave a more rapid and a higher extent of suppression than 1, 2 or 3 injections. Mice receiving only parasites, a glucose solution, starch particles or glucan^p by the i.p. route showed a progressive increase in footpad thickness and developed ulcerating lesions. An alkali solubilized glucan (glucan^as) was injected (50 μg, 200 μg and 400 μg/mousc) 4 times at 4 day intervals either i.v. or i.p. starling four days post parasite challenge. Glucan^as injection by either route blocked lesion development; the 50 μg treatment had already substantial effects and 400 μg in the i.p. route prevented even the initial stages of lesion formation. Touch prints from the lesion area and from the liver of mice receiving 200 μg glucan^as were amasiigote free. The anti Leishmania antibody litre of glucan^as treated mice was lower and their sera recognized fewer antigens than that of control Leishmania bearing mice.     

Chronic overproduction of islet amyloid polypeptide/amylin in transgenic mice: lysosomal localization of human islet amyloid polypeptide and lack of marked hyperglycaemia or hyperinsulinaemia

Summary Type 2 (non-insulin-dependent) diabetes mellitus is characterised by hyperglycaemia, peripheral insulin resistance, impaired insulin secretion and pancreatic islet amyloid formation. The major constituent of islet amyloid is islet amyloid polypeptide (amylin). Islet amyloid polypeptide is synthesized by islet beta cells and co-secreted with insulin. The ability of islet amyloid polypeptide to form amyloid fibrils is related to its species-specific amino acid sequence. Islet amyloid associated with diabetes is only found in man, monkeys, cats and racoons. Pharmacological doses of islet amyloid polypeptide have been shown to inhibit insulin secretion as well as insulin action on peripheral tissues (insulin resistance). To examine the role of islet amyloid polypeptide in the pathogenesis of Type 2 diabetes, we have generated transgenic mice with the gene encoding either human islet amyloid polypeptide (which can form amyloid) or rat islet amyloid polypeptide, under control of an insulin promoter. Transgenic islet amyloid polypeptide mRNA was detected in the pancreas in all transgenic mice. Plasma islet amyloid polypeptide levels were significantly elevated (up to 15-fold) in three out of five transgenic lines, but elevated glucose levels, hyperinsulinaemia and obesity were not observed. This suggests that insulin resistance is not induced by chronic hypersecretion of islet amyloid polypeptide. Islet amyloid polypeptide immunoreactivity was localized to beta-cell secretory granules in all mice. Islet amyloid polypeptide immunoreactivity in beta-cell lysosomes was seen only in mice with the human islet amyloid polypeptide gene, as in human beta cells, and might represent an initial step in intracellular formation of amyloid fibrils. These transgenic mice provide a unique model with which to examine the physiological function of islet amyloid polypeptide and to study intracellular and extracellular handling of human islet amyloid polypeptide in pancreatic islets.     

Myeloid differentiation is impaired in transgenic mice with targeted expression of a dominant negative form of retinoid X receptor β

To investigate the in vivo function of retinoid X receptor (RXR) on myelopoiesis, we generated transgenic (Tg) mice with targeted expression of a dominant negative form of RXR β in myeloid cells. In these Tg mice the transgene is expected to suppress the function of heterodimeric receptors composed of RXR and its counterparts, such as retinoic acid receptor. Out of 12 mice analysed, one Tg mouse exhibited a severe maturation arrest at the promyelocytic stage. Three other Tg mice showed a mild inhibition of myeloid differentiation, which was further augmented when mice were treated with 5-fluorouracil (5-FU). Furthermore, four Tg mice showed impaired myeloid differentiation in response to the treatment by 5-FU or granulocyte-colony stimulating factor (G-CSF), although they exhibited apparently normal myelopoiesis in the untreated state. The phenotype of Tg mice observed after G-CSF treatment correlated with the expression level of the transgene, although the correlation was not found in untreated mice. These results indicated that myeloid differentiation is perturbed in the Tg mice by the dominant negative effect of the transgenic RXR, indicating that RXR plays a role in myelopoiesis.     

藏药七十味珍珠丸对阿尔茨海默病转基因Tg2576鼠认知能力及脑羧基末端片段蛋白含量的影响

目的 探讨藏药七十味珍珠丸(ratanasampil,RNSP)对阿尔茨海默病(AD)模型鼠的学习和记忆功能、认知能力以及脑β淀粉样前体蛋白(amyloid precursor protein.APP)和羧基末端片段(C-terminal fragment,CTF)蛋白含量的影响. 方法 应用Y-迷宫明暗分辨学习和旷场实验观察13～14月龄雌性Tg2576转基因鼠和同龄雌性BL6/SJL非转基因(NTg)鼠的学习、记忆功能和行为学的变化.治疗组选取7只Tg2576鼠和5只NTg鼠用被溶解的RNSP灌胃8周,对照组选取8只Tg2576鼠和5只NTg鼠用蒸馏水和芝麻油混匀后灌胃8周.用抗8淀粉样蛋白(Ap)<,58>多克隆抗体WO<,2>和369抗体行蛋白印迹法测鼠血清Ap和脑的APP和CTF(α-、β、γ-CTF)蛋白含量并进行定量分析.应用免疫组织化学法观察Aβ在鼠脑中的表达. 结果治疗8周后,Y-迷宫结果显示,治疗组Tg2576鼠达标所需要的训练时间显著低于对照组Tg2576鼠[(34.2±9.7)s与(52.4±12.5)s,t=3.465,P<0.01].旷场试验结果显示.与对照组Tg2576鼠比较,治疗组Tg2576鼠在中央格停留时间明显减低,跨格次数和站立次数增加,排泄次数减少[(4.7±3.6)s与(12.9±9.0)s,(85.3±17.6)次与(54.3±13.9)次,(57.7±17.1)次与(20.6±17.4)次,(1.2±0.6)次与(3.4±0.9)次,t=5.871、8.200、3.093、2.231,均P<0.05].两对照组相比较,Tg2576鼠在中央格停留时间较NTg鼠长,跨格和站立次数较NTg鼠减少[(12.9±9.0)s与(5.2±5.9)s,(54.3±13.9)次与(85.8±22.5)次,(20.6±17.4)次与(53.5±14.0)次,均P<0.05].上述训练项目NTg鼠治疗组和对照组的差异均无统计学意义.蛋白印迹法结果显示,与对照组Tg2576鼠比较,RNSP治疗组Tg2576鼠血清Aβ含量显著减低(t=9.104,P<0.01),脑组织α-CTF蛋白的水平和α-CTF/β-CTF的比值明显增高(t=20.678、14.170,均P<0.01).但两组脑APP、β-CTF和γ-CTF蛋白无明显变化.免疫组化染色显示,治疗组Tg2576鼠的大脑皮质和海马周围Aβ淀粉样斑块的数目明显减少. 结论 RNSP能提高Tg2576鼠的学习和记忆能力,可能通过激动α分泌酶活性的APP非淀粉样酶切的代谢过程来增加鼠脑组织α-CTF蛋白的水平,降低血清Aβ浓度,使老年斑的形成减少.     

去痴灵对AD模型小鼠学习记忆及脑内突触体素表达的影响

目的 观察去痴灵对阿尔茨海默病(AD)小鼠学习记忆以及脑内突触体素(synaptophysin,SYN)表达的影响.方法 选用昆明种小鼠,右侧脑室注射β-淀粉样蛋白25-35(Aβ25-35)制备AD动物模型.造模1 w后,治疗组分别灌胃低、中、高剂量(3.05、6.10、12.20 g·kg~(-1)·d~(-1))去痴灵,以石杉碱甲为阳性对照药,连续28 d.给药结束后,对各组小鼠进行Morris水迷宫测试、脑组织SYN含量测定以及海马CA1区病理结构观察.结果 与模型组比较,去痴灵各剂量组均明显缩短水迷宫逃避潜伏期(P<0.05),中、高剂量组跨越平台次数显著增加(P<0.05);各治疗组AchE阳性纤维密度明显增加(P<0.05),脑内SYN含量明显升高(P<0.05),突触结构改善明显;各治疗组上述指标组间比较差异不显著(P>0.05).结论 去痴灵可明显改善Aβ所致的小鼠记忆障碍及突触丧失,其脑内突触再生,突触体素含量增加可能是去痴灵改善AD记忆的重要途径之一.