Serum Beta-Secretase 1 Activity Is a Potential Marker for the Differential Diagnosis between Alzheimer's Disease and Frontotemporal Dementia: A Pilot Study.

Alzheimer's disease (AD) and frontotemporal dementia (FTD) are the two major neurodegenerative diseases causing dementia. Due to similar clinical phenotypes, differential diagnosis is challenging without specific biomarkers. Beta-site Amyloid Precursor Protein cleaving enzyme 1 (BACE1) is a ß-secretase pivotal in AD pathogenesis. In AD and mild cognitive impairment subjects, BACE1 activity is increased in brain/cerebrospinal fluid, and plasma levels appear to reflect those in the brain. In this study, we aim to evaluate serum BACE1 activity in FTD, since, to date, there is no evidence about its role. The serum of 30 FTD patients and 30 controls was analyzed to evaluate (i) BACE1 activity, using a fluorescent assay, and (ii) Glial Fibrillary Acid Protein (GFAP) and Neurofilament Light chain (NfL) levels, using a Simoa kit. As expected, a significant increase in GFAP and NfL levels was observed in FTD patients compared to controls. Serum BACE1 activity was not altered in FTD patients. A significant increase in serum BACE1 activity was shown in AD vs. FTD and controls. Our results support the hypothesis that serum BACE1 activity is a potential biomarker for the differential diagnosis between AD and FTD.

Serum beta-secretase 1 (BACE1) activity increases in patients with mild cognitive impairment.

Beta-secretase 1 (BACE1) is considered as the key enzyme in amyloid-ß formation. Previous works suggest that high BACE1 activity may be present in brain, cerebrospinal fluid and serum of patients with late-onset Alzheimer's disease (LOAD) as well as mild cognitive impairment (MCI). Therefore, we evaluated whether serum BACE1 activity increases in MCI patients and is associated with the progression from MCI to dementia. BACE1 activity was measured in the serum of 259 MCI patients (162 amnestic-aMCI, 97 non-amnestic-naMCI) and 204 healthy Controls. After a median follow-up of 32 months (range: 10-153), 116 MCI progressed to dementia (87 aMCI and 29 naMCI). Serum BACE1 activity was higher in MCI compared with Controls (p < 0.001), and in aMCI with brain atrophy compared with naMCI without brain atrophy (p = 0.04). No difference in BACE1 activity emerged between converter and non-converter MCI, and this was true for both aMCI and naMCI. However, among aMCI with better cognitive performance (n. 163, MMSE score ≥24/30) those converting to dementia had higher BACE1 activity compared to stable ones (p = 0.05). This was not associated with an increased risk to develop dementia (hazard ratio: 1.65; 95% confidence interval: 0.67-4.01). In conclusion, serum BACE1 activity significantly increased in MCI patients (both amnestic and non-amnestic) compared with Controls. Moreover, higher serum BACE1 activity was observed only among aMCI with a better cognitive performance who progressed to dementia, suggesting that a dysregulation of this enzyme might be an early event primarily associated with neurodegeneration.

Establishment of a Sandwich-ELISA for simultaneous quantification of bovine pregnancy-associated glycoprotein in serum and milk.

Bovine pregnancy-associated glycoproteins (boPAG) are expressed by trophoblast cells in the bovine placenta. The multigene family of boPAG belongs to the group of aspartic proteases. The accumulation and circulation in maternal blood and milk has made boPAG very useful and important for pregnancy diagnosis in cattle. The goal of the present study was to develop and validate a new Sandwich-ELISA which allows the detection of boPAG in maternal serum and whole milk. Therefore, 984 serum and 928 milk samples were collected monthly from 231 Holstein Friesian cows (Bos Taurus) from one week after insemination (p.i.) until six weeks postpartum. The ELISA is able to identify a cow as being pregnant at day 30 p.i. in serum and at day 40 p.i in milk with threshold values of 1.0 ng/ml in serum and 0.0165 ng/ml in milk. The postpartum half-life of boPAG was estimated to be 6.4 days in serum and 7.1 days in milk. The boPAG profile established during pregnancy in serum and milk showed a typical pattern. The amount of boPAG found in milk was 1.5 % of the amount of boPAG present in serum. In conclusion, a Sandwich-ELISA has been developed to quantify boPAG in serum and in whole milk simultaneously with the same test procedure. This is time saving for farmers and more efficient for laboratories.

Plasma ß-secretase1 concentrations correlate with basal forebrain atrophy and neurodegeneration in cognitively healthy individuals at risk for AD.

BACKGROUND: Increased ß-secretase 1 (BACE1) protein concentration, in body fluids, is a candidate biomarker of Alzheimer's disease (AD).We reported that plasma BACE1 protein concentrations are associated with the levels of brain amyloidß (Αß) accumulation in cognitively healthy individuals with subjective memory complaint (SMC). METHODS: In 302 individuals from the same cohort, we investigated the cross-sectional and longitudinal association between plasma BACE1 protein concentrations and AD biomarkers of neurodegeneration (plasma t-tau and Neurofilament light chain (NfL), fluorodeoxyglucose-positron emission tomography (FDG-PET), brain volumes in the basal forebrain [BF], hippocampus, and entorhinal cortex). RESULTS: We report a positive longitudinal correlation of BACE1 with both NfL and t-tau, as well as a correlation between annual BACE1 changes and bi-annual reduction of BF volume. We show a positive association between BACE1 and FDG-PET signal at baseline. CONCLUSIONS: The association between plasma BACE1 protein concentrations and BF atrophy we found in cognitively healthy individuals with SMC corroborates translational studies, suggesting a role of BACE1 in neurodegeneration.

Relationship Between Alzheimer's Disease and Retinal Choroidal Thickness: A Cross-Sectional Study.

BACKGROUND: The choroid is involved directly or indirectly in many pathological conditions such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). OBJECTIVE: The objective of this study was to investigate the association between retinal choroidal properties and the pathology of AD by determining choroidal thickness, hippocampus volume, cognitive functions, and plasma BACE1 activity. METHODS: In this cross-sectional study, 37 patients with AD and 34 age-matched controls were included. Retinal choroidal thickness was measured via enhanced depth imaging optical coherence tomography. Hippocampal volume was measured via 3.0T MRI. Cognitive functions were evaluated using the Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog). Plasma BACE1 activity was analyzed using a fluorescence substrate-based plasma assay, and regression model were to analyze the data. RESULTS: Retinal choroidal thickness was significantly thinner in the AD group than in the control group [(114.81±81.30) µm versus (233.79±38.29) µm, p < 0.05]. Multivariable regression analysis indicated that the ADAS-cog scores (ß=-0.772, p = 0.000) and age (ß=-0.176, p = 0.015) were independently associated with choroidal thickness. The logistic regression model revealed that the subfoveal choroidal thickness was a significant predictor for AD (OR = 0.984, 95% CI: 0.972-0.997). CONCLUSION: There was a general tendency of choroid thinning as the cognitive function declined. Although choroidal thickness was not a potential indicator for early stage AD, it was valuable in monitoring AD progression.

Increased blood BACE1 activity as a potential common pathogenic factor of vascular dementia and late onset Alzheimer's disease.

Late onset Alzheimer disease (LOAD) is traditionally considered as a separate disease from vascular dementia (VAD). However, growing evidence suggests that ß-amyloid (Aß) accumulation, that initiates LOAD-related neurodegeneration, is preceded by vascular events. Previous in vitro studies showed that ß-secretase 1 (BACE1), the key-enzyme of amyloidogenesis, is upregulated by cerebrovascular insult; moreover, its activity is increased both in brain and serum of LOAD patients. We aimed to investigate whether BACE1 serum activity is altered also in dementias related, or not, to cerebrovascular disease. Thus, we evaluated serum BACE1 activity in a sample of individuals, including patients with LOAD (n. 175), VAD (n. 40), MIXED (LOAD/VAD) dementia (n. 123), other types of dementia (n. 56), and healthy Controls (n. 204). We found that BACE1 was significantly higher not only in LOAD (+ 30%), but also in VAD (+ 35%) and MIXED dementia (+ 22%) (p < 0.001 for all), but not in the other types of dementia (+ 10%). Diagnostic accuracy was 77% for LOAD, 83% for VAD, and 77% for MIXED dementia. In conclusion, we showed for the first time that the increase in peripheral BACE1 activity is a common feature of LOAD and VAD, thus underlying a further pathogenic link between these two forms of dementia.

BACE1 and Other Alzheimer's-Related Biomarkers in Cerebrospinal Fluid and Plasma Distinguish Alzheimer's Disease Patients from Cognitively-Impaired Neurosyphilis Patients.

BACKGROUND: Patients with spirochetal infection, which causes neurosyphilis (NS) and at a later stage general paresis of the insane (GPI), present with brain pathology features of Alzheimer's disease (AD). However, the relationships among these illnesses regarding biomarker levels are still unclear. OBJECTIVE: To explore biomarker levels in NS and GPI compared with those in AD and the relationship between biomarker levels and cognitive function in NS and GPI. METHODS: Levels of neurogranin (NGRN) and ß-amyloid precursor protein cleaving enzyme (BACE1) in cerebrospinal fluid (CSF)/plasma, together with amyloid-ß 1-40 (Aß40), Aß42, and total tau in the CSF of 23 AD patients, 55 GPI patients, and 13 NS patients were measured. Patients were classified into none-to-mild, moderate, and severe stages of cognitive impairment. RESULTS: Levels of CSF NGRN, BACE1, and tau as well as plasma BACE1 levels were significantly different among groups. In the none-to-mild stage, plasma BACE1 levels correlated with the protein levels in CSF and were significantly increased in AD patients versus GPI patients. The CSF tau levels in AD patients were significantly increased versus GPI patients in the moderate and severe stages. Pooling data from GPI and NS patients, both CSF tau and plasma NGRN levels correlated with cognitive scale scores. CONCLUSION: GPI and NS patients might have different biomarker level patterns compared to AD patients. While plasma BACE1 could be a promising early biomarker for distinguishing AD from GPI, CSF tau and plasma NGRN levels might be valuable in indications of cognitive function in pooled NS populations.

To study the effect of oxygen carrying capacity on expressed changes of erythrocyte membrane protein in different storage times.

Erythrocyte membrane is crucial to maintain the stability of erythrocyte structure. The membrane protein on the surface of erythrocyte membrane enables erythrocyte to have plasticity and pass through the microcirculation without being blocked or destroyed. Decreased deformability of erythrocyte membrane protein will lead to a series of pathological and physiological changes such as tissue and organ ischemia and hypoxia. Therefore, this research collected 30 cases of healthy blood donors, and explored erythrocyte stored at different times relating indicators including effective oxygen uptake (Q), P50, 2,3-DPG, Na+-k+-ATP. Erythrocyte morphology was observed by electron microscopy. Western blot and immunofluorescence assay were used to detect membrane protein EPB41, S1P, GLTP, SPPL2A expression changes of erythrocyte. To explore the effective carry oxygen capacity of erythrocyte at different storage time resulting in the expression change of erythrocyte surface membrane protein.

Associations of Plasma BACE1 Level and BACE1 C786G Gene Polymorphism with Cognitive Functions in Patients with Type 2 Diabetes: A Cross- Sectional Study.

BACKGROUND: ß-Site APP-cleaving enzyme 1 (BACE1) is a key enzyme involved in the pathophysiology of Type 2 Diabetes Mellitus (T2DM) and Mild Cognitive Impairment (MCI). We aimed to investigate the potential associations of plasma BACE1 levels and BACE1 gene polymorphism with different cognitive performances in T2DM patients with MCI. METHODS: The recruited 186 T2DM subjects were divided into 92 MCI group and 94 healthy-cognition controls, according to the Montreal Cognitive Assessment (MoCA) scores. Sociodemographic characteristics, clinical parameters and neuropsychological tests were assessed. BACE1 C786G gene polymorphism and plasma BACE1 level were determined. RESULTS: Compared to controls, MCI patients exhibited higher plasma BACE1 levels. Plasma BACE1 levels were negatively associated with MoCA, Clock Drawing Test and Logical Memory Test scores, whereas positively associated with Trail Making Test-B time in the MCI group (all p<0.05), after adjusting fasting blood glucose, glycosylated hemoglobin, and homeostasis model assessment of insulin resistance by C-peptide. Multivariable logistic regression analysis showed a significant trend towards increased MCI risk with high plasma BACE1 level in T2DM patients (OR = 1.492, p = 0.027). The plasma BACE1 levels of GG and GC genotypes were obviously higher than that of CC genotype in T2DM-MCI patients (p = 0.035; p = 0.026, respectively). CONCLUSION: Increased plasma BACE1 levels were associated with poor overall cognition functions, especially visuospatial abilities, visual/logical memory and executive functions in T2DM-MCI patients. Additionally, elevated plasma BACE1 level was a risk factor for MCI in T2DM patients, and might be influenced by BACE1 C786G gene mutations.

Sex differences in circulating neuregulin1-ß1 and ß-secretase 1 expression in childhood-onset schizophrenia.

OBJECTIVE: Early-onset schizophrenia is a severe and rare form of schizophrenia that is clinically and neurobiologically continuous with the adult form of schizophrenia. Neuregulin1 (NRG1)-mediated signaling is crucial for early neurodevelopment, which exerts its function by limited ß-secretase 1 (BACE1) proteolysis processing. However, circulating neuregulin1-ß1 (NRG1-ß1), an isoform of NRG1, and its cleavage enzyme BACE1 have not been studied in early-onset patients with schizophrenia. METHODS: In this study, we collected plasma and clinical information from 71 young patients (7 ≤ age years ≤20) with schizophrenia and 53 age- and sex-matched healthy controls. Immunoassay was used to test levels of circulating NRG1-ß1 and BACE1 expression. We further analyzed the relationship of disease-onset age and gender with NRG1-ß1 and BACE1 levels. RESULTS: We found that circulating plasma levels of NRG1-ß1 were significantly decreased in young patients with early-onset schizophrenia. In males with childhood onset schizophrenia (COS), NRG1-ß1 was reduced and was inversely correlated with positive symptom of PANSS; moreover, these male patients with higher plasma BACE1 levels showed more severe general symptoms of PANSS and defective social functioning; whereas, no aforementioned results were found in adolescent-onset schizophrenia (AOS). Notably, young female patients with COS and AOS had no significant change in NRG1-ß1 and BACE1, which demonstrated a sex-dependent effect in early-onset schizophrenia. CONCLUSION: Our results suggest that decreased levels of NRG1-ß1 and its cleavage enzyme BACE1 contribute to increased risk of etiology of schizophrenia. Synthetic biomarkers may have clinical applications for the early diagnosis of male COS.

Association of brain network dynamics with plasma biomarkers in subjective memory complainers.

Using a single integrated analysis, we examined the relationship between brain networks and molecular pathways in a cohort of elderly individuals at risk for Alzheimer's disease. In 205 subjective memory complainers (124 females, mean age: 75.7 ± 3.4), individual functional connectome was computed for a total of 3081 functional connections (set A) and 6 core plasma biomarkers of Alzheimer's disease (set B) were assessed. Partial least squares correlation analysis identified one dimension of population covariation between the 2 sets (p < 0.006), which we named bioneural mode. Five core plasma biomarkers and 190 functional connections presented bootstrap ratios greater than the critical value |1.96|. T-tau protein showed a trend toward significance (bootstrap resampling = 1.64). The salience, the language, the visuospatial, and the default mode networks were the strongest significant networks. We detected a strong association between network dynamics and core pathophysiological blood biomarkers. Innovative composite biomarkers, such as the bioneural mode, are promising to provide outcomes and better inform drug development and clinical practice for neurodegenerative diseases.

Brain Aß load association and sexual dimorphism of plasma BACE1 concentrations in cognitively normal individuals at risk for AD.

INTRODUCTION: Successful development of effective ß-site amyloid precursor protein cleaving enzyme 1 (BACE1)-targeted therapies for early stages of Alzheimer's disease requires biomarker-guided intervention strategies. METHODS: We investigated whether key biological factors such as sex, apolipoprotein E (APOE ε4) allele, and age affect longitudinal plasma BACE1 concentrations in a large monocenter cohort of individuals at risk for Alzheimer's disease. We explored the relationship between plasma BACE1 concentrations and levels of brain amyloid-ß (Aß) deposition, using positron emission tomography global standard uptake value ratios. RESULTS: Baseline and longitudinal mean concentrations of plasma BACE1 were significantly higher in women than men. We also found a positive significant impact of plasma BACE1 on baseline Aß-positron emission tomography global standard uptake value ratios. DISCUSSION: Our results suggest a sexual dimorphism in BACE1-related upstream mechanisms of brain Aß production and deposition. We argue that plasma BACE1 should be considered in further biomarker validation and qualification studies as well as in BACE1 clinical trials.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamic Effects of PF-06751979, a Potent and Selective Oral BACE1 Inhibitor: Results from Phase I Studies in Healthy Adults and Healthy Older Subjects.

PF-06751979 is a selective inhibitor of the beta-site amyloid precursor protein cleaving enzyme-1, which is a key aspartyl protease in the generation of amyloid-ß (Aß) peptides, thought to be critical for the cerebral degeneration observed in Alzheimer's disease. Two Phase I studies (NCT02509117, NCT02793232) investigated the safety/tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of PF-06751979. Single-ascending doses up to 540 mg and multiple-ascending doses up to 275 mg once daily (QD) in healthy adults, and multiple doses of 50 mg or 125 mg QD in healthy older subjects were assessed. PF-06751979 was well tolerated at all doses given, and all treatment-related adverse events (AEs) were mild to moderate. PK parameters remained consistent across the PF-06751979 QD dosing regimens, and no notable food effects were observed. PD analysis showed that PF-06751979 reduced the cerebrospinal fluid (CSF) and plasma levels of Aß peptides in a dose-dependent manner, with the greatest reductions observed in subjects treated with 275 mg QD (approximately 92% and 93% reduction in CSF Aß1-40 and Aß1-42 observed at 24 h after Day 14 dose, respectively). A drug interaction study (NCT03126721) using midazolam indicated that there was no clinically meaningful effect of multiple doses of PF-06751979 100 mg QD on the PK of single-dose midazolam in healthy adults. Overall, these data suggest that PF-06751979 with daily dosing is favorable for further clinical development.

Effects of vitamin D supplementation on cognitive function and blood Aß-related biomarkers in older adults with Alzheimer's disease: a randomised, double-blind, placebo-controlled trial.

OBJECTIVE: Our study aimed to assess the effect of a 12-month vitamin D supplementation on cognitive function and amyloid beta (Aß)-related biomarkers in subjects with Alzheimer's disease (AD). METHODS : This was a randomised, double-blind, placebo-controlled trial. 210 AD patients were randomly divided into intervention and control groups. Participants received 12-month 800 IU/day of vitamin D or starch granules as placebo. Tests of cognitive performance and Aß-related biomarkers were measured at baseline, 6 months and 12 months. RESULTS : Repeated-measures analysis of variance showed significant improvements in plasma Aß42, APP, BACE1, APPmRNA, BACE1mRNA (p<0.001) levels and information, arithmetic, digit span, vocabulary, block design and picture arrange scores (p<0.05) in the intervention group over the control group. According to mixed-model analysis, vitamin D group had significant increase in full scale IQ during follow-up period (p<0.001). CONCLUSIONS: Daily oral vitamin D supplementation (800 IU/day) for 12 months may improve cognitive function and decrease Aß-related biomarkers in elderly patients with AD. Larger scale longer term randomised trials of vitamin D are needed. TRIAL REGISTRATION NUMBER: ChiCTR-IIR-16009549.

Sex-based dimorphisms in expression of BDNF and BACE1 in bipolar patients.

Bipolar disorder (BD) is a chronic, serious mental disorder distinguished by repeated episodes of mania and depression. Previous studies have demonstrated dysregulation of a number of transcripts in brain tissue or peripheral blood of BD patients. In the present study, we compared expression of two protein coding genes (brain-derived neurotrophic factor (BDNF) and beta-secretase 1 (BACE1)) and their natural occurring anti-sense (AS) RNAs (BDNF-AS and BACE1-AS) in peripheral blood of 50 BD patients (mean age ±â€¯standard deviation (SD) = 36.5 ±â€¯9.32) and 50 healthy subjects (mean age ±â€¯SD = 33.62 ±â€¯8.59). BDNF and BACE1 were significantly up-regulated in peripheral blood of total BD patients compared with total healthy subjects (Expression ratio = 2.2, P value = 0.003; Expression ratio = 2.2, P value = 0.002 respectively). However, comparison of their levels in sex-based subgroups showed their up-regulations only in male patients compared with male health subjects (Expression ratio = 2.48, P value = 0.006; Expression ratio = 2.1, P value = 0.01). No significant differences were found in expressions of BDNF-AS and BACE1-AS between BD and health subjects. We detected a significant correlation between BDNF expression and age at disease onset in BD group after adjustment of the effects of sex (R = 0.26, P value = 0.03). Moreover, there were trends toward correlations between BDNF expression and disease duration in BD group and between BDNF expression and age in health subjects (P values = 0.05). Combination of BDNF, BDNF-AS and BACE1 expression levels could differentiate BD patients from healthy subjects with 68% sensitivity and 82% specificity (area under curve = 0.72, P value = 0.0001). The current study suggests a sex-based dimorphic pattern in expression of BDNF and BACE1. Moreover, our results imply that expression pattern of these genes could be diagnostic markers in BD. Future studies are needed to assess this speculation in larger patient samples.

Elevated cleavage of neuregulin-1 by beta-secretase 1 in plasma of schizophrenia patients.

Neuregulin 1 (NRG1) is a key candidate susceptibility gene for schizophrenia. It is reported that the function of NRG1 can be regulated by cleavage via the ß-Secretase (BACE1), particularly during early development. While current knowledge suggested that schizophrenia might have different phenotypes, it is unknown whether BACE1-cleaved-NRG1 (BACE1-NRG1) activity is related to clinical phenotypes of schizophrenia. In the current study, we used a newly developed enzymatic assay to detect BACE1-NRG1 activity in the human plasma and investigated the levels of cleavage of NRG1 by BACE1 in the plasma from schizophrenia patients. Our results are the first to demonstrate that the level of plasma BACE1-NRG1 activity was significantly increased in subjects affected with schizophrenia compared with healthy controls. Interestingly, the elevated BACE1-NRG1 activity was correlated with the disease severity and duration of schizophrenia, such as patients suffering from shorter-term course and worse disease status expressed higher BACE1-NRG1 activity levels compared to whom with longer duration and less severity of the disease. Furthermore, this is also the first report that the alternation of BACE1-NRG1 activity was a substrate -specific event in schizophrenia. Together, our findings suggested that the plasma BACE1-NRG1 activity can be a potential biomarker for the early diagnosis of schizophrenia.

Protein levels of ADAM10, BACE1, and PSEN1 in platelets and leukocytes of Alzheimer's disease patients.

The clinical diagnosis of Alzheimer's disease (AD) is a probabilistic formulation that may lack accuracy particularly at early stages of the dementing process. Abnormalities in amyloid-beta precursor protein (APP) metabolism and in the level of APP secretases have been demonstrated in platelets, and to a lesser extent in leukocytes, of AD patients, with conflicting results. The aim of the present study was to compare the protein level of the APP secretases A-disintegrin and metalloprotease 10 (ADAM10), Beta-site APP-cleaving enzyme 1 (BACE1), and presenilin-1 (PSEN1) in platelets and leukocytes from 20 non-medicated older adults with AD and 20 healthy elders, and to determine the potential use of these biomarkers to discriminate cases of AD from controls. The protein levels of all APP secretases were significantly higher in platelets compared to leukocytes. We found statistically a significant decrease in ADAM10 (52.5%, p < 0.0001) and PSEN1 (32%, p = 0.02) in platelets from AD patients compared to controls, but not in leukocytes. Combining all three secretases to generate receiver-operating characteristic (ROC) curves, we found a good discriminatory effect (AD vs. controls) when using platelets (the area under the curve-AUC-0.90, sensitivity 88.9%, specificity 66.7%, p = 0.003), but not in leukocytes (AUC 0.65, sensitivity 77.8%, specificity 50.0%, p = 0.2). Our findings indicate that platelets represent a better biological matrix than leukocytes to address the peripheral level of APP secretases. In addition, combining the protein level of ADAM10, BACE1, and PSEN1 in platelets, yielded a good accuracy to discriminate AD from controls.

Alterations in the Expression of Amyloid Precursor Protein Cleaving Enzymes mRNA in Alzheimer Peripheral Blood.

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia in elderly populations. Changes in the expression of the Amyloid Precursor Protein (APP)-cleaving enzymes directly affect the formation of Amyloid Beta (Aß) plaques, a neuropathological hallmark of AD. OBJECTIVE: We used peripheral blood from AD patients to investigate the expression of genes related to APP-processing [(ß-site APP-cleaving enzyme 1 (BACE1), presenilin1 (PSEN1), and a disintegrin and metalloproteinase family 10 (ADAM10) and 17 (ADAM17)] and the epigenetic genes sirtuin (SIRT)1-3, which regulate Aß production. METHOD: Real-time polymerase chain reactions were performed to determine the specific mRNA levels in plasma. The mRNA levels in AD patients were compared to those in healthy persons and assessed in relation to the subjects' cognitive performance. RESULTS: BACE1 mRNA level in AD subjects was significantly higher than those of healthy controls, whereas ADAM10 level was significantly lower in the AD subjects. The SIRT1 level was significantly decreased, while that of SIRT2 was increased in AD subjects and elderly controls compared to levels in healthy young control. In addition, correlations were found between the expression levels of BACE1, ADAM10 and SIRT1 and cognitive performance scores. Total Aß (Aß40+Aß42) levels and the Aß40/Aß42 ratio were significantly increased in the AD subjects, whereas decrease in plasma Aß42 was found in AD subjects. There was a negative correlation between Aß40 or total Aß and Thai Mental State Examination (TMSE) while there was no correlation between Aß40/Aß42 ratio or Aß42 and TMSE. CONCLUSION: The present findings provide evidence and support for the potential roles of these enzymes that drive Aß synthesis and for epigenetic regulation in AD progression and development, which can possibly be considered peripheral markers of AD.

Expression analysis of beta-secretase 1 (BACE1) and its naturally occurring antisense (BACE1-AS) in blood of epileptic patients.

Beta-secretase 1 (BACE1) gene encodes a transmembrane protease from the peptidase A1 family of aspartic proteases whose role in the pathogenesis of Alzheimer's disease has been assessed. The enzymatic activity of BACE1 on several proteins implicated in epileptogenesis implies its role in the pathogenesis of epilepsy. In the present study, we assessed expression of BACE1 and its naturally occurring antisense (BACE1-AS) in peripheral blood of 40 epileptic patients and 40 age- and sex-matched healthy subjects. We did not detect either any difference in the expression of these genes between cases and controls or significant correlation between their expressions and participants' age. However, we demonstrated a significant correlation between expression levels of BACE1 and BACE1-AS which supports the previously suggested feed-forward mechanism of regulation between these two transcripts. Future studies in larger sample sizes are needed to elaborate the function of BACE1 in epilepsy.

Plasma long non-coding RNA BACE1 as a novel biomarker for diagnosis of Alzheimer disease.

BACKGROUNDS: Long non-coding RNA (LncRNA) have been reported to be involved in the pathogenesis of neurodegenerative diseases, but whether it can serve as a biomarker for Alzheimer disease (AD) is not yet known. METHODS: The present study selected four specific LncRNA (17A, 51A, BACE1 and BC200) as possible AD biomarker. RT-qPCR was performed to validate the LncRNA. Receiver operating characteristic curve (ROC) and area under the ROC curve (AUC) were applied to study the potential of LncRNA as a biomarker in a population of 88 AD patients and 72 control individuals. RESULTS: We found that the plasma LncRNA BACE1 level of AD patients was significantly higher than that of healthy controls (p = 0.006). Plasma level of LncRNA 17A, 51A and BC200 did not show a significant difference between two groups (p = 0.098, p = 0.204 and p = 0.232, respectively). ROC curve analysis showed that LncRNA BACE1 was the best candidate of these LncRNA (95% CI: 0.553-0.781, p = 0.003). In addition, no correlation was found for expression of these LncRNA in both control and AD groups with age or MMSE scale (p > 0.05). CONCLUSIONS: Our present study compared the plasma level of four LncRNA between AD and non-AD patients, and found that the level of the BACE1 is increased in the plasma of AD patients and have a high specificity (88%) for AD, indicating BACE1 may be a potential candidate biomarker to predict AD.