Effect of memantine on expression of Bace1-as and Bace1 genes in STZ-induced Alzheimeric rats.

Recent studies have showed that the long non-coding RNAs (lncRNAs) expression is dysregulated in different neurodegenerative disorders like Alzheimer's disease (AD). In the present study, the effects of memantine on the level of Bace1-as and Bace1 genes' expression in streptozotocin (STZ)-induced Alzheimer's and memantine treated rats were investigated. The male Wistar rats were randomly divided into four groups: 1-Normal control, 2-Sham-operated control, 3- Alzheimer'scontrol rats (ICV-STZ), 4-Experimental group rats treated by memantine in a dose of 30 mg/kg/day for 28 days in ICV-STZ rats. The expression of Bace1-as and Bace1 genes was measured by quantitative-PCR in the brain and blood tissues. ELISA was used to analyze Bace1 and Aß proteins. Expression of Bace1-as was significantly increased in the brain and blood tissues of the experimental group (p = 0.032 and p = 0.034, respectively). The expression of Bace1 gene showed no significant changes in the brain. Furthermore, the ELISA analysis revealed that Bace1 protein was significantly increased in the plasma of the Alzheimer's control group (p = 0.000) and in the brain tissue of the experimental group (p = 0.000). Additionally, Aß levels had no significant changes between all groups studied. The Bace1 protein may be used as a prognostic biomarker in plasma, or before using memantine as a treatment. Furthermore, Bace1-as gene expression may play a role in monitoring the progression of AD.

Small interfering RNA delivery to the neurons near the amyloid plaques for improved treatment of Alzheimer׳s disease.

Gene therapy represents a promising treatment for the Alzheimer׳s disease (AD). However, gene delivery specific to brain lesions through systemic administration remains big challenge. In our previous work, we have developed an siRNA nanocomplex able to be specifically delivered to the amyloid plaques through surface modification with both CGN peptide for the blood-brain barrier (BBB) penetration and QSH peptide for ß-amyloid binding. But, whether the as-designed nanocomplex could indeed improve the gene accumulation in the impaired neuron cells and ameliorate AD-associated symptoms remains further study. Herein, we prepared the nanocomplexes with an siRNA against ß-site amyloid precursor protein-cleaving enzyme 1 (BACE1), the rate-limiting enzyme of Aß production, as the therapeutic siRNA of AD. The nanocomplexes exhibited high distribution in the Aß deposits-enriched hippocampus, especially in the neurons near the amyloid plaques after intravenous administration. In APP/PS1 transgenic mice, the nanocomplexes down-regulated BACE1 in both mRNA and protein levels, as well as Aß and amyloid plaques to the level of wild-type mice. Moreover, the nanocomplexes significantly increased the level of synaptophysin and rescued memory loss of the AD transgenic mice without hematological or histological toxicity. Taken together, this work presented direct evidences that the design of precise gene delivery to the AD lesions markedly improves the therapeutic outcome.

Association of G/C (rs638405) Polymorphism in ß-secretase Gene with Alzheimer's Disease.

BACKGROUND: Alzheimer's Disease (AD) is a neurodegenerative disorder, which is the most common cause of dementia in the elderly. Accumulation of ß-amyloid plaques outside neurons is the most important pathological hallmark of AD, which is produced by cleavage of amyloid precursor protein by the Alzheimer's ß-secretase (BACE1). Since BACE1 is a key enzyme in the formation of ß-amyloid peptides, the purpose of this study was to assess the association between polymorphisms of G/C (rs638405) BACE1 gene with sporadic AD in Khuzestan, Isfahan and Fars provinces in Iran. METHODS: Genotypes were determined by the PCR-Restriction Fragment Length Polymorphism (PCR-RFLP) technique in two groups including 89 sporadic AD patients and 73 healthy subjects. RESULTS: The findings of the BACE1 G/C (rs638405) polymorphism revealed that there was no significant difference between AD patients and controls in men group; however, there was a weak difference in the frequency of CC genotype between patients and controls in women group (χ 2=3.333, df=1, p=0.068). CONCLUSION: The results of this study suggest that the G/C (rs638405) polymorphism of BACE1 gene might not be related with sporadic AD in Khuzestan, Isfahan and Fars provinces in Iran. However, our results do not support a genetic risk factor of this polymorphism for developing AD in male group of this study.

Meta-analysis of BACE1 gene rs638405 polymorphism and the risk of Alzheimer's disease in Caucasion and Asian population.

Recent studies showed the ß-site amyloid precursor protein cleaving enzyme (BACE) is associated with Alzheimer's disease (AD). However, studies investigating the association of single-nucleotide polymorphism (SNP) in exon 5 of BACE1 (rs638405, C786G, Val262) with AD are controversial. Therefore we conducted this meta-analysis to clarify the association. Relevant studies were identified on PubMed, Cochrane library and CNKI from established through July 2015 according to the inclusion criteria. Odds ratios (ORs) with 95% confidence intervals (CIs) and five genetic models were applied to assess the association. A total of 13 studies composed of 2538 AD patients and 3020 controls were included in this study. Significant association of SNP rs638405 with AD was found in overall population among allelic genetic model (G vs. C: OR=1.11, 95%CI=1.02-1.20, P=0.01), codominant genetic model (GG vs. CC: OR=1.22, 95%CI=1.04-1.44, P=0.02) and recessive genetic model (GG vs. GC+ CC: OR=1.25, 95%CI=1.10-1.42, P=0.0008). Besides, subgroup analysis indicated significant association among Asian population (allelic genetic model, G vs. C, OR=1.18, 95%CI=1.04-1.34, P=0.01; codominant genetic model, GG vs. CC, OR=1.43, 95%CI=1.08-1.89, P=0.01 and recessive genetic model, GG vs. GC+ CC, OR=1.40, 95%CI=1.09-1.78, P=0.008) and Caucasion population (recessive genetic model, GG vs. GC+ CC, OR=1.20, 95%CI=1.02-1.39, P=0.02). Our analysis demonstrated that GG genotype and G allele of BACE1 gene rs638405 probably increase the risk of AD.

Small interfering RNA delivery to the neurons near the amyloid plaques for improved treatment of Alzheimer׳s disease

Gene therapy represents a promising treatment for the Alzheimer׳s disease (AD). However, gene delivery specific to brain lesions through systemic administration remains big challenge. In our previous work, we have developed an siRNA nanocomplex able to be specifically delivered to the amyloid plaques through surface modification with both CGN peptide for the blood-brain barrier (BBB) penetration and QSH peptide for -amyloid binding. But, whether the as-designed nanocomplex could indeed improve the gene accumulation in the impaired neuron cells and ameliorate AD-associated symptoms remains further study. Herein, we prepared the nanocomplexes with an siRNA against -site amyloid precursor protein-cleaving enzyme 1 (BACE1), the rate-limiting enzyme of A production, as the therapeutic siRNA of AD. The nanocomplexes exhibited high distribution in the A deposits-enriched hippocampus, especially in the neurons near the amyloid plaques after intravenous administration. In APP/PS1 transgenic mice, the nanocomplexes down-regulated BACE1 in both mRNA and protein levels, as well as A and amyloid plaques to the level of wild-type mice. Moreover, the nanocomplexes significantly increased the level of synaptophysin and rescued memory loss of the AD transgenic mice without hematological or histological toxicity. Taken together, this work presented direct evidences that the design of precise gene delivery to the AD lesions markedly improves the therapeutic outcome.