Chronic Sleep Restriction Induces Cognitive Deficits and Cortical Beta-Amyloid Deposition in Mice via BACE1-Antisense Activation.

AIMS: To clarify the correlation between chronic sleep restriction (CSR) and sporadic Alzheimer disease (AD), we determined in wild-type mice the impact of CSR, on cognitive performance, beta-amyloid (Aß) peptides, and its feed-forward regulators regarding AD pathogenesis. METHODS: Sixteen nine-month-old C57BL/6 male mice were equally divided into the CSR and control groups. CSR was achieved by application of a slowly rotating drum for 2 months. The Morris water maze test was used to assess cognitive impairment. The concentrations of Aß peptides, amyloid precursor protein (APP) and ß-secretase 1 (BACE1), and the mRNA levels of BACE1 and BACE1-antisense (BACE1-AS) were measured. RESULTS: Following CSR, impairments of spatial learning and memory consolidation were observed in the mice, accompanied by Aß plaque deposition and an increased Aß concentration in the prefrontal and temporal lobe cortex. CSR also upregulated the ß-secretase-induced cleavage of APP by increasing the protein and mRNA levels of BACE1, particularly the BACE1-AS. CONCLUSIONS: This study shows that a CSR accelerates AD pathogenesis in wild-type mice. An upregulation of the BACE1 pathway appears to participate in both cortical Aß plaque deposition and memory impairment caused by CSR. BACE1-AS is likely activated to initiate a cascade of events that lead to AD pathogenesis. Our study provides, therefore, a molecular mechanism that links CSR to sporadic AD.

Interleukin-1ß Promoter Polymorphism Enhances the Risk of Sleep Disturbance in Alzheimer's Disease.

Sleep alleviates Alzheimer's disease (AD)-related neuropathological processes, whereas sleep disturbance in AD patients is associated with elevated peripheral inflammatory cytokine levels. In the present study, we assessed interleukin (IL)-1ß and APOEε4 polymorphisms for association with susceptibility of sleep disturbances in AD patients. A total of 123 pretreated AD patients and 120 age-, gender- and education level-matched healthy controls were recruited for two consecutive full-night polysomnography and measurement of Epworth Sleepiness Scale (ESS) scores for sleep-wake disturbance. Their genomic DNA was analyzed for IL-1ß and APOEε4 SNPs using ligase detection reaction (LDR) technology. Blood levels of IL-1ß, IL-6, and tumor necrosis factor alpha (TNF-α) were measured using ELISA after lipopolysaccharide (LPS) stimulation. The odds ratio and 95% confidence interval for genotype-specific risk were calculated using an unconditional logistic regression model and adjusted by age, gender, educational levels, body mass index (BMI), and activities of daily living (ADL). Compared to the non-APOEε4/ε4 genotype, APOEε4/ε4 significantly increased the risk of AD (APOEε4/ε4 vs. non-APOEε4/ε4, adjusted OR = 4.33, 95% CI = 1.33-14.10, p = 0.015). Compared to the IL-1ß CC genotype (-31), the TT genotype significantly increased the risk of AD (TT vs. CC, adjusted OR = 1.72, 95% CI = 1.13-2.61, p = 0.010). AD patients carrying the APOEε4 allele and the IL-1ß TT genotype showed less time in bed, longer sleep latency and REM latency, more awakenings, and a lower SWS percentage than those carrying CC/CT combined genotypes. In addition, blood IL-1ß levels were significantly greater in AD patients carrying both the APOEε4 allele and the IL-1ß-31TT genotype than in those carrying the APOEε4 allele and the -31 TC or CC genotype. In conclusion, this study provides the first evidence indicating that the IL-1ß-31TT genotype and homozygous APOEε4 combined are associated with increased risk of developing AD with sleep disturbance.

Low-Dose Atypical Antipsychotic Risperidone Improves the 5-Year Outcome in Alzheimer's Disease Patients with Sleep Disturbances.

Sleep disturbances (SD) accelerate the progression of Alzheimer's disease (AD) and increase the stress of caregivers. However, the long-term outcome of disturbed nocturnal sleep/wake patterns in AD and on increased stress of spousal caregivers is unclear. This study assessed the 5-year effect of nocturnal SD on the long-term outcome in AD patients. A total of 156 donepezil-treated mild-moderate AD patients (93 AD + SD and 63 AD - SD as a control group) were recruited. The AD + SD patients were formed into 4 subgroups according to the preferences of spousal caregivers for treatment with atypical antipsychotics (0.5-1 mg risperidone, n = 22), non-benzodiazepine hypnotic (5-10 mg zolpidem tartrate, n = 33), melatonin (2.55 mg, n = 9), or no-drug treatment (n = 29). SD were evaluated by polysomnography, sleep scale, and cognitive scale examinations. Moreover, all spousal caregivers of AD patients were assessed using a series of scales, including sleep, anxiety, mood, and treatment attitude scales. Our data showed that nocturnal sleep/wake disturbances were significantly associated with lower 5-year outcomes for AD patients, earlier nursing home placement, and more negative emotions of spousal caregivers. Treatment with low-dose atypical antipsychotic risperidone improved the 5-year outcome in AD + SD patients. In conclusion, low-dose atypical antipsychotic risperidone improves the 5-year outcome in AD patients with SD. Moreover, improvement of nocturnal sleep problems in AD patients will also bring better emotional stability for AD caregivers.

Calcineurin contributes to spatial memory impairment induced by rapid eye movement sleep deprivation.

Recent evidence suggests that rapid eye movement (REM) sleep deprivation (REMSD) causes learning and memory deficits. However, the mechanism of REMSD-induced memory impairment remains unclear. Calcineurin (CaN) is involved in synaptic plasticity and is known as a negative constraint on learning and memory. Here we report that 72 h REMSD by the modified multiple platform method in rats resulted in spatial memory impairment in the Morris water maze and elevated hippocampal cytosolic CaN activity, both of which were reversed after 18 h sleep recovery. CaN expression in the whole-tissue homogenate of the hippocampus was not altered by REMSD. The results suggest that elevated hippocampal CaN activity is involved in REMSD-induced spatial memory impairment.

[Molecular characters of Centella asiatica found with RAPD technology].

OBJECTIVE: To analyze the DNA molecular characters of Centella asiatica with RAPD technology. METHODS: With the genomic DNA as templates extracted from various source of Centella asiatica samples, optimized RAPD PCR reaction systems had been used. The random promers had been screened to amplify the specific molecular fragments of Centella asiatica. RESULTS: The specific genetic bands of Centella asiatica species from various habitats were established which were highly stable and repeatable and obviously different from those of other families, genuses of plants such as Gynostemma pentaphylum, Tobacco, Cayratia japonica. CONCLUSION: The developed method of RAPD analysis for the genetic character bands of Centella asiatica could be applied to identify real Centella asiatica from its spurious breed plants. The genetic character bands of Centella asiatica amplified with the RAPD method show high homogeneous in several samples from different habitats.