Chronic sleep deprivation exacerbates cognitive and pathological impairments in APP/PS1/tau triple transgenic Alzheimer's disease model mice / 生理学报

Sleep exerts important functions in the regulation of cognition and emotion. Recent studies have found that sleep disorder is one of the important risk factors for Alzheimer's disease (AD), but the effects of chronic sleep deprivation on the cognitive functions of AD model mice and its possible mechanism are still unclear. In the present study, 8-month-old male APP/PS1/tau triple transgenic AD model (3xTg-AD) mice and wild type (WT) mice (n = 8 for each group) were subjected to chronic sleep deprivation by using the modified multiple platform method, with 20 h of sleep deprivation each day for 21 days. Then, open field test, elevated plus maze test, sugar water preference test, object recognition test, Y maze test and conditioned fear memory test were performed to evaluate anxiety- and depression-like behaviors, and multiple cognitive functions. In addition, the immunohistochemistry technique was used to observe pathological characteristics in the hippocampus of mice. The results showed that: (1) Chronic sleep deprivation did not affect anxiety- (P = 0.539) and depression-like behaviors (P = 0.874) in 3xTg-AD mice; (2) Chronic sleep deprivation exacerbated the impairments of object recognition memory (P < 0.001), working memory (P = 0.002) and the conditioned fear memory (P = 0.039) in 3xTg-AD mice; (3) Chronic sleep deprivation increased amyloid β (Aβ) deposition (P < 0.001) and microglial activation (P < 0.001) in the hippocampus of 3xTg-AD mice, without inducing abnormal tau phosphorylation and neurofibrillary tangles. These results indicate that chronic sleep deprivation exacerbates the impairments of recognition memory, working memory and conditioned fear memory in 3xTg-AD mice by aggravating Aβ deposition and the excessive activation of microglia in the hippocampus.

Early / 中南大学学报(医学版)

Alzheimer's disease (AD) is the most common senile neurodegenerative disease characterized by progressive cognitive dysfunction, psychological and behavioral abnormalities, and impaired ability of activities of daily living. A family with a total of 3 patients were admitted to the Department of Neurology of Xiangya Hospital, Central South University in 2018. The proband showed memory decline as the presenting symptoms, and subsequently showed psychological and behavioral abnormalities, personality changes, seizures, and motor retardation. Definite diagnosis of early-onset familial AD (EOFAD) with missense mutation of presenilin 2 (PSEN2) (c.715A>G p.M239V) was established by whole exome sequencing (WES) technology. We reported the mutation in Chinese Han population for the first time, which expanded the mutation spectrum ofPSEN2 gene and aid to enrich the characterization of clinical phenotype in EOFAD associated to PSEN2 mutations. Patients with early onset age and complex clinical manifestations of AD can be diagnosed with the help of genetic testing to avoid misdiagnosis.

Contributing Factors to Diabetic Brain Injury and Cognitive Decline

The link of diabetes with co-occurring disorders in the brain involves complex and multifactorial pathways. Genetically engineered rodents that express familial Alzheimer's disease-associated mutant forms of amyloid precursor protein and presenilin 1 (PSEN1) genes provided invaluable insights into the mechanisms and consequences of amyloid deposition in the brain. Adding diabetes factors (obesity, insulin impairment) to these animal models to predict success in translation to clinic have proven useful at some extent only. Here, we focus on contributing factors to diabetic brain injury with the aim of identifying appropriate animal models that can be used to mechanistically dissect the pathophysiology of diabetes-associated cognitive dysfunction and how diabetes medications may influence the development and progression of cognitive decline in humans with diabetes.

PSEN1 p.Met233Val in a Complex Neurodegenerative Movement and Neuropsychiatric Disorder

Mutations in presenilin 1 (PSEN1) are the most common cause of autosomal dominant Alzheimer's disease. Here, we report a Canadian-Vietnamese family carrying a PSEN1 p.Met233Val mutation with an exceptionally early and severe presentation that includes a wide range of atypical symptoms, including prominent ataxia, Parkinsonism, spasticity, dystonia, action tremor, myoclonus, bulbar symptoms, seizures, hallucinations and behavioral changes. Whole-exome sequencing (WES) was performed on the affected proband after many assessments over several years proved diagnostically inconclusive. The results were analyzed using the AnnEx “Annotated Exomes” browser (http://annex.can.ubc.ca), a web-based platform that facilitates WES variant annotation and interpretation. High-throughput sequencing can be especially informative for complex neurological disorders, and WES warrants consideration as a first-line clinical test. Data analyses facilitated by web-based bioinformatics tools have great potential for novel insight, although confirmatory, diagnostically accredited Sanger sequencing is recommended prior to reporting.

Sex Differences in Neuropathology and Cognitive Behavior in APP/PS1/tau Triple-Transgenic Mouse Model of Alzheimer's Disease / 神经科学通报·英文版

Alzheimer's disease (AD) is the most common form of dementia among the elderly, characterized by amyloid plaques, neurofibrillary tangles, and neuroinflammation in the brain, as well as impaired cognitive behaviors. A sex difference in the prevalence of AD has been noted, while sex differences in the cerebral pathology and relevant molecular mechanisms are not well clarified. In the present study, we systematically investigated the sex differences in pathological characteristics and cognitive behavior in 12-month-old male and female APP/PS1/tau triple-transgenic AD mice (3×Tg-AD mice) and examined the molecular mechanisms. We found that female 3×Tg-AD mice displayed more prominent amyloid plaques, neurofibrillary tangles, neuroinflammation, and spatial cognitive deficits than male 3×Tg-AD mice. Furthermore, the expression levels of hippocampal protein kinase A-cAMP response element-binding protein (PKA-CREB) and p38-mitogen-activated protein kinases (MAPK) also showed sex difference in the AD mice, with a significant increase in the levels of p-PKA/p-CREB and a decrease in the p-p38 in female, but not male, 3×Tg-AD mice. We suggest that an estrogen deficiency-induced PKA-CREB-MAPK signaling disorder in 12-month-old female 3×Tg-AD mice might be involved in the serious pathological and cognitive damage in these mice. Therefore, sex differences should be taken into account in investigating AD biomarkers and related target molecules, and estrogen supplementation or PKA-CREB-MAPK stabilization could be beneficial in relieving the pathological damage in AD and improving the cognitive behavior of reproductively-senescent females.

Reproduction,genotype identification and evaluation of APP/PS1 transgenic mice / 中国应用生理学杂志

OBJECTIVES@#To identify the genotype of (APP/PS1) transgenic mice and evaluate the changing of cognitive and behavioral fu nctions, provide an effective animal model for the Alzheimer's disease (AD) research.@*METHODS@#Male APP/PS1 transgenic mice mated with female APP/PS1 transgenic mice, and the genotype of their filial mice was identified by PCR. The APP +/PS1 + mice were assigned into AD model group (AD group, =8), and the APP/PS1 mice were assigned into control group (CT group, =8). The Morris water maze test was carried out to detect the capacity of learning and memory of mice. After that, the mice were sacrificed and the brain tissues were sampled and stained by HE and congo red for the pathological examination.@*RESULTS@#①A APP/PS1 genome DNA about 360 bp size was detected. The methods of feeding and breeding were successful to attain APP/PS1 transgenic mice.②Statistical significance was found in the differences of the capacity of learning and memory between 7-month-old APP/PS1 positive mice and negative mice (<0.05).③The results of HE stain showed that the structure and cellular morphology of hippocampus of AD mice were obviously abnormal. The results of congo red stain showed that positive amyloid plaque was observed in brains of AD mice.@*CONCLUSIONS@#APP/PS1 transgenic mice present typical symptoms and behaviors of Alzheimer's disease. The transgenic mouse is an effective tool for the research and prevention of AD.

iPSC Modeling of Presenilin1 Mutation in Alzheimer's Disease with Cerebellar Ataxia

Disease modeling of Alzheimer's disease (AD) has been hampered by the lack of suitable cellular models while animal models are mainly based on the overexpression of AD-related genes which often results in an overemphasis of certain pathways and is also confounded by aging. In this study, we therefore developed and used induced pluripotent stem cell (iPSC) lines from a middle-aged AD patient with a known presenilin 1 (PSEN1) mutation (Glu120Lys; PS1-E120K) and as a control, an elderly normal subject. Using this approach, we demonstrated that the extracellular accumulation of Aβ was dramatically increased in PS1-E120K iPSC-derived neurons compared with the control iPSC line. PS1-E120K iPSC-derived neurons also exhibited high levels of phosphorylated tau, as well as mitochondrial abnormalities and defective autophagy. Given that the effect of aging is lost with iPSC generation, these abnormal cellular features are therefore indicative of PSEN1-associated AD pathogenesis rather than primary changes associated with aging. Taken together, this iPSC-based approach of AD modeling can now be used to better understand AD pathogenesis as well as a tool for drug discovery.

Huannao Yicong Formula () regulates γ-secretase activity through APH-1 and PEN-2 gene ragulation pathways in hippocampus of APP/PS1 double transgenic mice / 中国结合医学杂志

<p><b>OBJECTIVE</b>To observe the effects of Huannao Yicong Formula (, HYF) on learning and memory and it's regulating effect on γ-secretase related anterior pharynx defective 1 (APH-1), presenilin enhancer-2 (PEN-2) signaling pathway, so as to discuss and further clarify the mechanism of HYF on Alzheimer's disease.</p><p><b>METHODS</b>Sixty APP/PS1 transgenic mice, randomly allocated into 4 groups, the model group, the donepezil group (0.65 mg/kg), HYF low-dose group (HYF-L, 5.46 g/kg) and HYF high-dose group (HYF-H, 10.92 g/kg), 15 for each group. Another 15 C57BL/6J mice with the same age and same genetic background were allocated into the control group, proper dosage of drugs or distilled water were given by intragastric administration once daily for 12 weeks. After 12 weeks of administration, the learning and memory abilities of mice in each group was evaluated by the morris water maze test, amyloid precursor protein (APP), Aβand Aβlevels in hippocampus were detected by enzyme-linked immunosorbent assay, γ-secretase was detected by dual luciferase assaying, the levels of APH-1a, hypoxia-inducible factor 1α (HIF-1α), cAMP response element-binding protein (CREB) and PEN-2 and their mRNA expression was measured by Western blot and real-time polymerase chain reaction.</p><p><b>RESULTS</b>HYF can ameliorate learning and memory deficits in APP/PS1 transgenic mice by decreasing the escape latency, improving the number of platform crossing and swimming speed (P<0.01, P<0.05). HYF can decrease the levels of APP, Aβ, Aβand the activity of γ-secretase in hippocampus of Alzheimer's disease model mice. HYF can down-regulate the levels of CREB and PEN-2 and the expression of their mRNA.</p><p><b>CONCLUSION</b>HYF can improve the learning and memory ability by inhibiting the activity of γ-secretase through the CREB/PEN-2 signaling pathway, and this may be one of the therapeutic mechanisms of HYF in Alzheimer's disease.</p>

Nicotinamide Reduces Amyloid Precursor Protein and Presenilin 1 in Brain Tissues of Amyloid Beta-Tail Vein Injected Mice

The purpose of this study is to investigate whether nicotinic acid (NA) and nicotinamide (NAM) reduce the Alzheimer disease (AD)-related gene expression in brain tissues of amyloid beta (Aβ)-injected mice. Male Crj:CD1 (ICR) mice were divided into 6 treatment groups; 1) control, 2) Aβ control, 3) Aβ + NA 20 mg/kg/day (NA20), 4) Aβ + NA40, 5) Aβ + NAM 200 mg/kg/day (NAM200), and 6) Aβ + NAM400. After 1-week acclimation period, the mice orally received NA or NAM once a day for a total of 7 successive days. On day 7, biotinylated Aβ42 was injected into mouse tail vein. At 5 hours after the injection, blood and tissues were collected. Aβ42 injection was confirmed by Western blot analysis of Aβ42 protein in brain tissue. NAM400 pre-treatment significantly reduced the gene expression of amyloid precursor protein and presenilin 1 in brain tissues. And, NAM200 and NAM400 pre-treatments significantly increased sirtuin 1 expression in brain tissues, which is accompanied by the decreased brain expression of nuclear factor kappa B by 2 doses of NAM. Increased expression of AD-related genes was attenuated by the NAM treatment, which suggests that NAM supplementation may be a potential preventive strategy against AD-related deleterious changes.

Mutation analysis of presenilin 1 gene in a Chinese family affected with early-onset familial Alzheimer's disease / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To explore the clinical phenotype and genotype in a Chinese family affected with early-onset familial Alzheimer's disease (EOFAD).</p><p><b>METHODS</b>Potential mutation of beta-amyloid precursor protein (APP) gene, presenilin 1 (PSEN1) gene and apolipoprotein E (APOE) gene was detected with polymerase chain reaction (PCR) and direct sequencing.</p><p><b>RESULTS</b>Homozygous APOE ε 2 allele and no gene mutation of APP gene were detected in the proband (III1). A 488A>G mutation (His163Arg) of the PSEN1 gene was found in the proband and other 4 family members (IV1, IV12, IV21, V2).</p><p><b>CONCLUSION</b>A mutation (c.488A>G, p.His163Arg) of PSEN1 gene was found in a Chinese family affected with EOFAD.</p>

Descripción genotípica y fenotípica de la enfermedad de Alzheimer tardía y familiar precoz: revisión / Genotypic and phenotypic description of late-onset Alzheimer's disease and early onset familial Alzheimer's: Review / Descrição genotípica e fenotípica da doença de Alzheimer tardia e familiar precoce: revisão

La demencia es la pérdida de varias áreas del funcionamiento cognitivo respecto al nivel premórbido, con deterioro significativo en la funcionalidad. La más común es ocasionada por la enfermedad de Alzheimer, que se define como un trastorno neurodegenerativo que produce una alteración progresiva de la memoria y de otras habilidades mentales, por una pérdida de volumen en los lóbulos temporales, en especial en las áreas mediales como el hipocampo y la corteza entorrinal. Menos del 5% de los pacientes con esta enfermedad presenta formas hereditarias que pueden tener un inicio precoz (antes de los 65 años) o tardío (después de dicha edad). La EA precoz presenta un patrón de herencia autosómico dominante y puede ser causado por mutaciones en el gen de la proteína precursora de amiloide, en presenilina-1 o presenilina-2. Los casos de EA tardía, están influenciados por una genética compleja, con múltiples factores de susceptibilidad y el alelo ApoE4 es el principal y más reconocido. La EA es una enfermedad heterogénea tanto en su genotipo como en su fenotipo que varían en cuanto a intensidad y tipo de síntomas, edad de inicio y severidad de la demencia, de acuerdo con las mutaciones que el paciente presenta y su interacción con factores ambientales.

Dementia is known as the loss of multiple areas of cognitive function with respect to a premorbid condition, involving a significant deterioration in functionality. The most common subtype is Alzheimer's disease, which is defined as a neurodegenerative disorder that causes a progressive deterioration in memory and other mental capacities due to volume loss in temporal lobes, especially in mesial aspects, such as the hippocampus and the entorhinal cortex. Approximately 5% of patients affected by this disease have a hereditary form, with an early onset (before 65 years) or a late onset (after 65 years). Early onset Alzheimer's disease has a genetic autosomal dominant inheritance pattern, which can be caused by mutations in the gene encoding for the amyloid precursor protein, presenilin-1, or presenilin-2. In the cases of late onset Alzheimer's disease, there is a complex genetic influence, with multiple susceptibility factors, where the ApoE4 allele is the main and most recognized factor. Alzheimer's disease is a heterogeneous dementia, both in genotype and phenotype, varying in intensity and symptoms, age of onset, and severity of the disease, depending on the different mutations that a patient may have and the interactions with environmental factors.

A demência é a perda de várias áreas do funcionamento cognitivo com respeito ao nível pré-mórbido, com deterioro significativo na funcionalidade. A mais comum é ocasionada pela doença de Alzheimer, que se define como um transtorno neurodegenerativo que produz uma alteração progressiva da memória e de outras habilidades mentais, por uma perda de volume nos lóbulos temporais, em especial nas áreas mediais como o hipocampo e o córtex entorrinal. Menos de 5% dos pacientes com esta doença apresenta formas hereditárias que podem ter um início precoce (antes dos 65 anos) ou tardio (depois de dita idade). A D.A. precoce apresenta um padrão de herança autossômico dominante e pode ser causado por mutações no gene da proteína precursora de amiloide, em presenilina-1 ou presenilina-2. Os casos de D.A. tardia, estão influenciados por uma genética complexa, com múltiplos fatores de susceptibilidade e o alelo ApoE4 é o principal e mais reconhecido. A D.A. é uma doença heterogénea tanto em seu genótipo como em seu fenótipo que variam em quanto a intensidade e tipo de sintomas, idade de inicio e severidade da demência, de acordo com as mutações que o paciente apresenta e sua interação com fatores ambientais.

Comparison of clinical bracket point registration with 3D laser scanner and coordinate measuring machine

OBJECTIVE: The aim of the present study was to assess the diagnostic value of a laser scanner developed to determine the coordinates of clinical bracket points and to compare with the results of a coordinate measuring machine (CMM). METHODS: This diagnostic experimental study was conducted on maxillary and mandibular orthodontic study casts of 18 adults with normal Class I occlusion. First, the coordinates of the bracket points were measured on all casts by a CMM. Then, the three-dimensional coordinates (X, Y, Z) of the bracket points were measured on the same casts by a 3D laser scanner designed at Shahid Beheshti University, Tehran, Iran. The validity and reliability of each system were assessed by means of intraclass correlation coefficient (ICC) and Dahlberg's formula. RESULTS: The difference between the mean dimension and the actual value for the CMM was 0.0066 mm. (95% CI: 69.98340, 69.99140). The mean difference for the laser scanner was 0.107 ± 0.133 mm (95% CI: -0.002, 0.24). In each method, differences were not significant. The ICC comparing the two methods was 0.998 for the X coordinate, and 0.996 for the Y coordinate; the mean difference for coordinates recorded in the entire arch and for each tooth was 0.616 mm. CONCLUSION: The accuracy of clinical bracket point coordinates measured by the laser scanner was equal to that of CMM. The mean difference in measurements was within the range of operator errors. .

OBJETIVO: o objetivo do presente estudo foi avaliar o valor diagnóstico de um scanner a laser desenvolvido para determinar as coordenadas dos pontos de colagem de braquetes, comparando seus resultados aos resultados obtidos com uma máquina de medição coordenada (MMC). MÉTODOS: esse estudo experimental diagnóstico foi conduzido com modelos ortodônticos obtidos a partir da arcada superior de 18 pacientes adultos, com oclusão normal de Classe I. Inicialmente, as coordenadas dos pontos de colagem de braquetes de todos os modelos foram mensuradas por uma MMC. Em seguida, as coordenadas tridimensionais (X, Y, Z) dos pontos foram mensuradas nos mesmos modelos por um scanner a laser 3D, desenvolvido na Universidade de Shahid Beheshti. A eficácia e confiabilidade dos dois sistemas foram avaliadas pelo Coeficiente de Correlação Intraclasse (CCI) e pela fórmula de Dahlberg. RESULTADOS: a diferença entre a média da dimensão mensurada pela MMC e o valor real obtido foi de 0,0066mm (IC 95%: 69,98340 - 69,99140). A diferença média para o scanner a laser foi de 0,107 ± 0,133 (95% IC: -0,002 - 0,24). Em cada método, as diferenças não foram significativas. Ao comparar os dois métodos, o CCI gerou um valor de 0,998 para a coordenada X e de 0,996 para a coordenada Y. A diferença média para as coordenadas registradas em cada dente da arcada foi de 0,616mm. CONCLUSÃO: a precisão das coordenadas do ponto de colagem dos braquetes foi a mesma no scanner a laser e na MMC. A diferença média entre as medições manteve-se dentro dos limites de erros operacionais. .

Study of mutations of presenilin 1 gene in early-onset familial Alzheimers disease / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>Mutations of presenilin 1 (PSEN1) gene are the most frequent cause for familial Alzheimers disease (AD). This study was set to explore potential mutation of PSEN1 gene in a Chinese family featuring early-onset Alzheimers disease (FAD).</p><p><b>METHODS</b>DNA was isolated from peripheral blood samples from 17 members of the FAD family as well as 10 patients with sporadic Alzheimers disease and 100 healthy subjects. With polymerase chain reaction (PCR) and Sanger sequencing, exons 113 of the PSEN1 gene were analyzed.</p><p><b>RESULTS</b>DNA sequencing has revealed a heterozygous point mutation from G to A at position 1133 (Gly378Glu) of exon 11 of PSEN1 gene in 6 members from the family, among whom 5 were patients with dementia, whilst the remaining 1 was clinically normal but under onset age. The same mutation was not found in all other patients and the normal controls.</p><p><b>CONCLUSION</b>A novel missense mutation of the PSEN1 gene, Gly378Glu, probably underlies the autosomal dominant early-onset FAD in this Chinese family.</p>

Effects of huannao yicong recipe extract on the learning and memory and related factors of Abeta generation in the brain of APP transgenic mice / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To study the effects of Huannao Yicong Recipe (HNYCR)extract on the learning and memory ability, and the expressions of amyloid precursor protein (APP), beta-site APP-cleaving enzyme 1 (BACE1), presenilin-1 (PS-1), and beta amyloid protein (Abeta)in hippocampus CA1 area of APP transgenic mice, and to explore its mechanisms for treating Alzheimer's disease (AD).</p><p><b>METHODS</b>Totally 3-month-old APP695V7171 transgenic mice were used to establish the AD model in this research. They were randomly divided into the model group, the Donepezil group, the large dose HNYCR extract group, the small dose HNYCR extract group, and the normal control group (C57BL/6J mice), 15 in each group. These animals were gavaged for 4 continuous months. Relevant indicators were detected: Morris water maze test was used to measure the spatial learning and memory ability. The immunohistochemical assay was used to detect the expressions of APP, BACE1, PS-1, and Abeta.</p><p><b>RESULTS</b>The times of crossing the original platform and the swimming time and distance in the fourth quadrant of the 7-month-old APP transgenic mice were significantly reduced in Morris water maze test, when compared with the normal control group (P < 0.01). The times of crossing original platform and the swimming time and distance in the fourth quadrant of all treatment groups significantly increased in Morris water maze test, when compared with the model group (P < 0.05). The expressions of APP, BACE1, PS-1, and Abeta in hippocampus CA1 area of 7-month-old model mice increased significantly (P < 0.01), when compared with the normal control group. The expressions of APP, BACE1, PS-1, and Abeta in each 7-month-old intervention groups were significantly reduced, when compared with the model group (P < 0.01).</p><p><b>CONCLUSION</b>Early application of HNYCR extract can obviously improve the learning and memory ability of APP transgenic mice that has declined, reduce the expressions of APP, BACE1, PS-1, and Abeta in the hippocampal CA1 area, reduce the production of Abeta, and slow down the pathological process of brains in APP transgenic mice.</p>

Generation of Tau/App/PS1 triple-transgenic mouse model and the study of its biological characteristics / 中国应用生理学杂志

<p><b>OBJECTIVE</b>To establish the triple-transgenic mouse model and study their biological characteristics by molecular biology, behavior and pathology.</p><p><b>METHODS</b>Hybrid the Tau and amyloid precursor protein (APP)/presenilins (PS1) transgenic mouse, the genotype of offspring mice were identified by PCR. Transcribed target genes were detected by RT-PCR. The protein expression of exogenous genes was detected by Western-blot. The pathological change of neurofibrillary tangles and senile plaque were observed by Bielschowsky silver staining and ABC immunohistochemical method. The changes time of learning and memory were observed by Morris water maze.</p><p><b>RESULTS</b>APP, PS1 and Tau genes were transcript in Tau/APP/PS1 mice. In 6 to 8 months old Tau/APP/PS1 mice, the neurofibrillary tangles and senile plaque could be found in cortex and hippocampus. In 6 months old Tau/APP/PS1 mice, the learning and memory abilities were worse.</p><p><b>CONCLUSION</b>With the behavior change and pathological changes in Tau and beta-amyloid protein (AP), the Tau/APP/PS1 triple-transgenic mice can be used as a further study animal model of AD's pathogenesis and the target of drug treatment.</p>

Effect of curcumin on synapse-related protein expression of APP/PS1 double transgenic mice / 中国中药杂志

<p><b>OBJECTIVE</b>To observe the effect of curcumin on the expression of synapse-related proteins PSD-95 and Shank1 in APP/PS1 double transgenic mice.</p><p><b>METHOD</b>Three-month-old APP/PS1 dtg mice were randomly divided into the model group, the positive Rosiglitazone control group and curcumin high (400 mg x kg(-1) x d(-1)), medium (200 mg x kg(-1) x d(-1)) and low (100 mg x kg(-1) x d(-1)) dose groups, with non-genetically modified mice with the same background as the normal group. After the oral administration for three months, immunohistochemistry and Western blot were adopted for detection.</p><p><b>RESULT</b>According to the behavioral detection, the treatment group and the model group showed differences in the place navigation test and the spatial probe test to varying degrees (P < 0.01 or P < 0.05). The expression of PSD-95 and Shank1-positive cells of hippocampus CA1 region significantly decreased in model mice compared with normal control group (P < 0.01); while the curcumin intervention group showed recovery to some extend. Western blot results showed that the strap of PSD-95 protein expression became significantly thinner and lighter in the model group compared with the normal control group (P < 0.01); while the curcumin intervention group showed notably thicker and darker straps of PSD-95 protein expression (P < 0.05).</p><p><b>CONCLUSION</b>Curcumin can increase the expression of synapse-related proteins PSD95 and Shank1 in APP/PS1 double transgenic mice, improve structure and plasticity of synapse in APP/PS1 double transgenic mice and enhance their learning and memory abilities.</p>

Expression of the plant viral protease NIa in the brain of a mouse model of Alzheimer's disease mitigates Abeta pathology and improves cognitive function

The plant viral protease, NIa, has a strict substrate specificity for the consensus sequence of Val-Xaa-His-Gln, with a scissoring property after Gln. We recently reported that NIa efficiently cleaved the amyloid-beta (Abeta) peptide, which contains the sequence Val-His-His-Gln in the vicinity of the cleavage site by alpha-secretase, and that the expression of NIa using a lentiviral system in the brain of AD mouse model reduced plaque deposition levels. In the present study, we investigated whether exogenous expression of NIa in the brain of AD mouse model is beneficial to the improvement of cognitive deficits. To address this question, Lenti-NIa was intracerebrally injected into the brain of Tg-APPswe/PS1dE9 (Tg-APP/PS1) mice at 7 months of age and behavioral tests were performed 15-30 days afterwards. The results of the water maze test indicated that Tg-APP/PS1 mice which had been injected with Lenti-GFP showed an increased latency in finding the hidden-platform and markedly enhanced navigation near the maze-wall, and that such behavioral deficits were significantly reversed in Tg-APP/PS1 mice injected with Lenti-NIa. In the passive avoidance test, Tg-APP/PS1 mice exhibited a severe deficit in their contextual memory retention, which was reversed by NIa expression. In the marble burying test, Tg-APP/PS1 mice buried marbles fewer than non-transgenic mice, which was also significantly improved by NIa. After behavioral tests, it was verified that the Tg-APP/PS1 mice with Lenti-NIa injection had reduced Abeta levels and plaque deposition when compared to Tg-APP/PS1 mice. These results showed that the plant viral protease, NIa, not only reduces Abeta pathology, but also improves behavioral deficits.

Intracerebroventricular transplantation of human amniotic epithelial cells ameliorates spatial memory deficit in the doubly transgenic mice coexpressing APPswe and PS1ΔE9-deleted genes / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Human amniotic epithelial cells (HAECs), which have characteristics of both embryonic and pluripotent stem cells, are therefore a candidate in cell therapy without creating legal or ethical problems. In the present study, we aimed to investigate the effects of intracerebroventricular transplantation of HAECs on doubly transgenic mice of Alzheimer's disease (AD) coexpressing presenilin-1 (PS1) and mutant Sweden amyloid precursor protein (APPswe) genes.</p><p><b>METHODS</b>The offspring mice genotypes were detected using PCR identification of APPswe and PS1 gene. The doubly transgenic (TG) mice (n = 20) and wild-type (WT) mice (n = 20) were randomly divided into two groups respectively: the transplantation group treated with HAECs and the control group with phosphate buffered saline. Six radial arm water maze test was used to assess the spatial memory in the TG and WT mice. Amyloid plaques and neurofibrillary tangles were analyzed using congo red and acid-silver methenamine staining respectively. Immunofluorescence cytochemistry was used to track the survival of HAECs. Immunohistochemistry was used to determine the expression of octamer-binding protein 4 (Oct-4) and Nanog in the HAECs. High performance liquid chromatography was used to measure acetylcholine in hippocampus. The density of cholinergic neurons in basal forebrain and nerve fibers in hippocampus was measured using acetylcholinesterase staining.</p><p><b>RESULTS</b>Amyloid deposition occurred in hippocampus and frontal cortex in the double TG mice aged 8 months, but not in WT mice. The results also showed that transplanted HAECs can survive for at least 8 weeks and migrate to the third ventricle without immune rejection. The graft HAECs can also express the specific marker Oct-4 and Nanog of stem cell. Compared with the control group, transplantation of HAECs can not only significantly improve the spatial memory of the TG mice, but also increase acetylcholine concentration and the number of hippocampal cholinergic neurites.</p><p><b>CONCLUSIONS</b>These results demonstrate that intracerebroventricular transplantation of HAECs can improve the spatial memory of the double TG mice. The higher content of acetylcholine in hippocampus released by more survived cholinergic neurites is one of the causes of this improvement.</p>

Perfil clínico y cognitivo de la atrofia cortical posterior y sus diferencias con la enfermedad de Alzheimer esporádica tardía y familiar precoz / Clinical and cognitive profile of posterior cortical atrophy and its differences with late sporadic and early familial Alzheimer's disease

Introducción. La atrofia cortical posterior (ACP) es una demencia focal que se manifiesta al inicio con trastornos cognitivos posteriores, principalmente alteración visuoperceptual por el daño en la corteza occipitoparietal, lo que permite en la clínica diferenciarla de la enfermedad de Alzheimer (EA). Objetivos. Analizar y comparar el rendimiento cognitivo de pacientes con ACP y con EA. Materiales y métodos. La muestra estuvo formada por los siguientes grupos: cuatro pacientes con ACP, siete con EA familiar precoz, nueve con EA esporádica tardía y cuatro controles sanos. A cada participante se le aplicó un protocolo de evaluación neuropsicológica para valorar procesos cognitivos y funcionalidad. La comparación entre grupos se realizó utilizando la prueba no paramétrica U de Mann-Whitney. Resultados. Los pacientes con ACP obtuvieron puntuaciones significativamente inferiores en praxias constructivas e ideacionales, lectura, cálculo y visuopercepción, respecto a ambos grupos de EA. Por el contrario, en memoria verbal, fluidez semántica y función ejecutiva, el grupo con ACP presentó mejor desempeño. Conclusión. Al inicio del proceso neurodegenerativo la clínica de la ACP se diferencia de la de EA. La ACP es una demencia con características sintomatológicas propias y no sólo una variante de la EA, aunque ambas compartan el mismo sustrato histopatológico.

Introduction. Posterior cortical atrophy (PCA) is a focal dementia manifested by posterior cognitive disorders, initially visuoperceptual alterations due to damage in occipito-parietal cortex, which permits PCA to be clinicallydifferentiated of Alzheimer's Disease (AD). Objetive. To analize and to compare cognitive performance of patients with PCA and with AD. Materials and methods. Sample was conformed by the following groups: four patients with PCA, seven with early familial AD, nine with late sporadic AD and four healthy controls. A neuropsychological examination battery was administrated to each participant in order to assess cognitive processes and functionality. Between-groups comparisons were made by using U Mann-Whitney non parametric test.Results. Patients with PCA had significantly lower scores in constructional and ideational praxias, reading, calculation andvisuoperception, compared to both AD groups. In contrast, PCA group showed better performance in verbal memory,semantic fluency and executive function.Conclusion. At the beginning of neurodegenerative process, PCA symptomatology is clearly different of that presented in AD. PCA is a dementia with particular symptomatic characteristics and not only a variant of AD, even if both share the same hystopathological substrate.

Oxidative damage increased in presenilin1/presenilin2 conditional double knockout mice / 神经科学通报·英文版

<p><b>OBJECTIVE</b>This report aims to describe the oxidative damage profile in brain of presenilin1 and presenilin2 conditional double knockout mice (dKO) at both early and late age stages, and to discuss the correlation between oxidative stress and the Alzheimer-like phenotypes of dKO mice.</p><p><b>METHODS</b>The protein level of Abeta(42) in dKO cortex and free 8-OHdG level in urine were measured by ELISA. Thiobarbituric acid method and spectrophotometric DNPH assay were used to determine the lipid peroxidation and protein oxidation in cortex, respectively. SOD and GSH-PX activities were assessed by SOD Assay Kit-WST and GSH-PX assay kit, separately.</p><p><b>RESULTS</b>Significant decrease of Abeta(42) was verified in dKO cortex at 6 months as compared to control mice. Although lipid peroxidation (assessed by MDA) was increased only in dKO cortex at 3 months and protein oxidation (assessed by carbonyl groups) was basically unchanged in dKO cortex, ELISA analysis revealed that free 8-OHdG, which was an indicator of DNA lesion, was significantly decreased in urine of dKO mice from 3 months to 12 months. Activities of SOD and GSH-PX in dKO and control cortices showed no statistical difference except a significant increase of GSH-PX activity in dKO mice at 9 months.</p><p><b>CONCLUSION</b>Oxidative damage, especially DNA lesion, was correlated with the neurodegenerative symptoms that appeared in dKO mice without the deposition of Abeta(42). Triggers of oxidative damage could be the inflammatory mediators released by activated microglia and astrocytes.</p>