Association of HbA1c with functional outcome by ischemic stroke subtypes and age.

Objectives: To determine whether high HbA1c levels are related to short-and long-term functional outcomes in patients with ischemic stroke (IS) and whether this association differs according to the IS subtype and the patient's age. Methods: The data of 7,380 IS patients admitted to 16 hospitals or regional stroke centers in South-Korea, between May 2017 and December 2019, were obtained from the Clinical Research Collaboration for Stroke-Korea-National Institute of Health database and retrospectively analyzed. Among these patients, 4,598 were followed-up for one-year. The HbA1c levels were classified into three groups (<5.7, 5.7 to <6.5%, ≥6.5%). Short-and long-term poor functional outcomes were defined using the modified Rankin Scale score of 2 to 6 at three-months and one-year, respectively. IS subtypes were categorized according to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification. Results: There was an association between higher HbA1c (≥6.5%) and poor functional outcomes at three-months in all patients (three-months; OR, 1.299, 95% CI 1.098, 1.535, one-year; OR, 1.181, 95% CI 0.952, 1.465). When grouped by age, the associations after both 3 months and 1 year observed in younger adult group (<65 years), but not in group aged 65 years and older (three-months; <65 years OR, 1.467, 95% CI 1.112, 1.936, ≥65 years OR, 1.220, 95% CI 0.987, 1.507, p for interaction = 0.038, one-year; <65 years OR, 1.622, 95% CI 1.101, 2.388, ≥65 years OR, 1.010, 95% CI 0.778, 1.312, p for interaction = 0.018). Among younger adult group, the higher HbA1c level was related to short-and long-term functional loss in patients with the small vessel occlusion subtype (three-months; OR, 2.337, 95%CI 1.334, 4.095, one-year; OR, 3.004, 95% CI 1.301, 6.938). However, in patients with other TOAST subtypes, a high HbA1c level did not increase the risk of poor outcomes, regardless of the age of onset. Conclusion: High HbA1c levels increase the risk of short-and long-term poor functional outcomes after IS onset. However, this association differs according to stroke subtype and age. Thus, pre-stroke hyperglycemia, reflected by HbA1c, may be a significant predictor for a poor prognosis after ischemic stroke, particular in young- and middle-aged adults.

Gender differences in mortality and long-term functional outcomes after first-ever ischemic stroke: A prospective cohort study.

BACKGROUND: Although many studies about survival rates and functional outcomes after stroke have been published, studies on gender differences have reported conflicting results. AIMS: To determine whether there are differences in mortality and functional outcomes during the first 5 years after a first-ever ischemic stroke in Korean males and females. METHOD: This is an interim analysis of the Korean Stroke Cohort for Functioning and Rehabilitation, a prospective multicenter cohort study. Multifaceted functional assessments were performed repeatedly from 7 days to 60 months after stroke onset to test motor, ambulatory, cognitive, language, and swallowing functions as well as activities of daily living (ADLs) in patients with first-ever stroke. Of 10,636 first-ever-stroke patients admitted to nine representative hospitals in Korea, 8210 were ischemic stroke patients included in the mortality analysis. Among them, 6258 patients provided informed consent and 3508 completed functional assessments for 60 months. Gender-related differences in 5-year mortality and functional recovery were analyzed. RESULT: Women showed a significantly higher 5-year mortality rate than men after correction for possible covariates (p < 0.05). In terms of functional outcomes, women showed worse ambulatory, cognitive, language, and ADL outcomes than men after adjusting for covariates (all p < 0.05). The 5-year recovery pattern differed significantly between genders only for ADL function (ß-coefficient estimate = 0.34; p = 0.03). CONCLUSION: Five-year mortality rate, functional outcomes, and recovery patterns after first-ever ischemic stroke differed significantly by gender. These results suggest the need for gender-specific stroke care and long-term management strategies.

Association of Blood Cadmium with Cardiovascular Disease in Korea: From the Korea National Health and Nutrition Examination Survey 2008-2013 and 2016.

Cardiovascular disease (CVD) is the leading cause of death globally, although the mortality rate has declined with improved technology and risk factor control. The incidence rate of stroke, one of the CVDs, is increasing in young adults, whereas it is decreasing in the elderly. The risk factors for CVD may differ between young adults and the elderly. Previous studies have suggested that cadmium was a potential CVD risk factor in the overall and middle-aged to elderly populations. We assessed the associations between cadmium and CVD events in the Korean population aged 20-59 years using the 2008-2013 and 2016 Korea National Health and Nutrition Examination Survey (KNHANES), a population-based cross-sectional study. Among 10,626 participants aged 20-59 years, those with high blood cadmium (BCd) level (>1.874 µg/L, 90th percentile) were higher associated with stroke and hypertension (stroke: odds ratio (OR), 2.39; 95% confidence interval (CI), 1.03-5.56; hypertension: OR, 1.46; 95% CI, 1.20-1.76). The strongest association between high blood cadmium concentrations and hypertension was among current smokers. Ischemic heart disease (IHD) was not associated with high blood cadmium level. These findings suggest that high blood cadmium levels may be associated with prevalent stroke and hypertension in the Korean population under 60 years of age.

Association between blood lead level and risk of stroke in Korean adults: a cross-sectional study in the Korea National Health and Nutrition Examination Survey 2008-2013.

OBJECTIVES: Although lead is a potential risk factor for cardiovascular diseases such as stroke, research on this association in the Korean population remains limited. Therefore, we aimed to investigate the association between lead level and stroke in Korean adults. DESIGN: A population-based cross-sectional study. SETTING: The Korea National Health and Nutrition Examination Survey 2008-2013, which enrolled a representative sample of the Korean population. PARTICIPANTS: We excluded participants younger than 20 years, missing weight data, pregnant or lactating, and missing blood lead and stroke data. A total of 11 510 participants were included in this analysis. PRIMARY AND SECONDARY OUTCOME MEASUREMENT: The participants were classified by blood lead concentration into the low-level (≤2.189 µg/dL, n=5756) and high-level (>2.189 µg/dL, n=5754) groups. The main outcome, stroke, was assessed by information from physician diagnosis, prevalence of stroke or treatment for stroke. The ORs and 95% CIs were calculated to evaluate the association between blood lead level and stroke using multivariate logistic regression analysis. RESULTS: Although blood lead level was not significantly associated with stroke (OR: 1.30, 95% CI: 0.66-2.58) in the multivariate-adjusted model, in individuals with hypertension, the high-level group was 2.36-fold higher odds of stroke (OR: 2.36, 95% CI: 1.02-5.44) compared to that in the low-level group. No association was observed in individuals with normotension (OR: 0.42, 95% CI: 0.13-1.38, p for interaction=0.007). CONCLUSION: The association between blood lead concentration and stroke may be influenced by hypertension status. Our findings suggest the need for closer attention to lead exposure in patients with hypertension.

Elevated Cerebrospinal Fluid and Plasma N-Cadherin in Alzheimer Disease.

N-cadherin is a synaptic adhesion molecule stabilizing synaptic cell structure and function. Cleavage of N-cadherin by γ-secretase produces a C-terminal fragment, which is increased in the brains of Alzheimer disease (AD) patients. Here, we investigated the relationship between fluid N-cadherin levels and AD pathology. We first showed that the cleaved levels of N-cadherin were increased in homogenates of postmortem brain from AD patients compared with that in non-AD patients. We found that cleaved N-cadherin levels in the cerebrospinal fluid were increased in AD dementia compared with that in healthy control. ELISA results revealed that plasma levels of N-cadherin in 76 patients with AD were higher than those in 133 healthy control subjects. The N-cadherin levels in the brains of an AD mouse model, APP Swedish/PS1delE9 Tg (APP Tg) were reduced compared with that in control. The N-terminal fragment of N-cadherin produced by cleavage at a plasma membrane was detected extravascularly, accumulated in senile plaques in the cortex of an APP Tg mouse. In addition, N-cadherin plasma levels were increased in APP Tg mice. Collectively, our study suggests that alteration of N-cadherin levels might be associated with AD pathology.

Factors Associated with Changes in Functional Independence after Six Months of Ischemic Stroke.

The aim of this study is to investigate the changes in functional independence and their associated factors during the first 6 months to 1 year after stroke onset. This study is the interim results of the Korean Stroke Cohort for Functioning and Rehabilitation. A total of 1,011 participants were included and classified into 3 subgroups according to changes in the Korean version of Modified Barthel Index (K-MBI) scores that occurred between 6 months to 1 year after stroke onset: the improved group (IG), with scores that increased 5 points or more; the stationary group (SG), with the K-MBI score changes ranging from -4 to +4 points; and the declined group (DG), with the K-MBI scores that decreased 5 points or more. Ordinal logistic regression analyses were used to assess the factors influencing changes in the K-MBI score. Among 1,011 patient, 436 patients (43.1%), 398 patients (39.4%) and 117 patients (17.5%) were classified into the IG, SG, and DG, respectively. Obesity and Geriatric Depression Scale score were significant influencing factors for changes in the K-MBI scores. Obesity showed a positive influence on the K-MBI score, while depression showed a negative influence.

Elevation of plasma soluble amyloid precursor protein beta in Alzheimer's disease.

INTRODUCTION: Beta-amyloid is considered to be a pathophysiological marker in Alzheimer's disease (AD). Soluble amyloid precursor proteins (sAPPs) -α (sAPPα) and -ß (sAPPß), which are the byproducts of non-amyloidogenic and amyloidogenic process of APP, respectively, have been repeatedly observed in the cerebrospinal fluids (CSF) of AD patients. The present study focused on the determination of sAPP levels in peripheral blood. METHODS: The plasma protein levels of sAPPα and sAPPß were measured with ELISA. Plasma from 52 AD patients, 98 amnestic mild cognitive impairment (MCI) patients, and 114 cognitively normal controls were compared. RESULTS: The plasma level of sAPPß was significantly increased in AD patients than in cognitively healthy controls. However, no significant change in plasma sAPPα was observed among the three groups. Furthermore, the plasma sAPPß levels significantly correlated with cognitive assessment scales, such as clinical dementia rating (CDR), and mini-mental status examination (MMSE). Interestingly, sAPPα and sAPPß had a positive correlation with each other in blood plasma, similar to previous studies on CSF sAPP. This correlation was stronger in the MCI and AD groups than in the cognitively healthy controls. CONCLUSIONS: These results suggest that individuals with elevated plasma sAPPß levels are at an increased risk of AD; elevation in these levels may reflect the progression of disease.

Altered expression of Notch1 in Alzheimer's disease.

Notch signaling is an evolutionarily conserved pathway that regulates cell-cell interactions through binding of Notch family receptors to their cognate ligands. Notch signaling has an essential role in vascular development and angiogenesis. Recent studies have reported that Notch may be implicated in Alzheimer's disease (AD) pathophysiology. We measured the levels of soluble Notch1 (sNotch1) in the plasma samples from 72 dementia patients (average age 75.1 y), 89 subjects with amnestic mild cognitive impairment (MCI) (average age 73.72 y), and 150 cognitively normal controls (average age 72.34 y). Plasma levels of sNotch1 were 25.27% lower in dementia patients as compared to healthy control subjects. However, the level of Notch1 protein was significantly increased in human brain microvascular endothelial cells (HBMECs) after amyloid-beta treatment. Also, Notch1 mRNA level was significantly increased in HBMECs and iPSC-derived neuronal cells from AD patient compared to normal control. These results indicate that altered expression of Notch1 might be associated with the risk of Alzheimer's disease.

Association of plasma endothelial lipase levels on cognitive impairment.

BACKGROUND: Peripheral high-density lipoprotein cholesterol (HDL-C) has been known to influx into the brain and be inversely associated with the risk of Alzheimer's disease (AD). However, recent prospective studies of the association between HDL-C and AD have yielded inconsistent results. Here, we examined the association between the endothelial lipase (EL), which is known to be major determinant of HDL-C levels, and cognitive function. METHOD: We compared plasma from 20 patients with Alzheimer's disease (AD), 38 persons with mild cognitive impairment, and 51 cognitively normal controls. Plasma EL levels were measured using the enzyme-linked immunosorbent assay. RESULTS: EL levels were inversely correlated with HDL-C, as previously reported; however, there were no mean differences in plasma EL between the diagnostic groups. An analysis by classification of dementia severity according to clinical dementia rating (CDR) showed that the EL levels were significantly higher in the CDR1 group (mild dementia), as compared to CDR0 (no dementia), CDR0.5 (very mild), and CDR2 (moderate) groups. Prior to moderate dementia stage, trends analysis showed that EL levels tended to increase with increasing severity (p for trend = 0.013). Consistently, elevated EL levels were significantly correlated with the mini-mental state examination (MMSE) score (r = - 0.29, p = 0.003). Logistic regression for association between plasma EL and cognitive impairment (MMSE score ≤ 25) showed that participants with EL levels in the upper range (> 31.6 ng/ml) have a higher adjusted odds ratio of cognitive impairment than those within the lower EL range. CONCLUSION: Findings from the present study reflect the association of EL and cognition, suggesting that the individuals with elevated plasma EL concentration are at an increased risk of cognitive impairment.

Different Brain Connectivity between Responders and Nonresponders to Dual-Mode Noninvasive Brain Stimulation over Bilateral Primary Motor Cortices in Stroke Patients.

Noninvasive brain stimulation (NBS), such as repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS), has been used in stroke patients with motor impairment. NBS can help recovery from brain damage by modulating cortical excitability. However, the efficacy of NBS varies among individuals. To obtain insights of responsiveness to the efficacy of NBS, we investigated characteristic changes of the motor network in responders and nonresponders of NBS over the primary motor cortex (M1). A total of 21 patients with subacute stroke (13 males, mean age 59.6 ± 11.5 years) received NBS in the same manner: 1 Hz rTMS on the contralesional M1 and anodal tDCS on the ipsilesional M1. Participants were classified into responders and nonresponders based on the functional improvement of the affected upper extremity after applying NBS. Twelve age-matched healthy controls (8 males, mean age 56.1 ± 14.3 years) were also recruited. Motor networks were constructed using resting-state functional magnetic resonance imaging. M1 intrahemispheric connectivity, interhemispheric connectivity, and network efficiency were measured to investigate differences in network characteristics between groups. The motor network characteristics were found to differ between both groups. Specifically, M1 intrahemispheric connectivity in responders showed a noticeable imbalance between affected and unaffected hemispheres, which was markedly restored after NBS. The responders also showed greater interhemispheric connectivity and higher efficiency of the motor network than the nonresponders. These results may provide insight on patient-specific NBS treatment based on the brain network characteristics in neurorehabilitation of patients with stroke. This trial is registered with trial registration number NCT03390192.

Fisetin stimulates autophagic degradation of phosphorylated tau via the activation of TFEB and Nrf2 transcription factors.

The neuronal accumulation of phosphorylated tau plays a critical role in the pathogenesis of Alzheimer's disease (AD). Here, we examined the effect of fisetin, a flavonol, on tau levels. Treatment of cortical cells or primary neurons with fisetin resulted in significant decreases in the levels of phosphorylated tau. In addition, fisetin decreased the levels of sarkosyl-insoluble tau in an active GSK-3ß-induced tau aggregation model. However, there was no difference in activities of tau kinases and phosphatases such as protein phosphatase 2A, irrespective of fisetin treatment. Fisetin activated autophagy together with the activation of transcription factor EB (TFEB) and Nrf2 transcriptional factors. The activation of autophagy including TFEB is likely due to fisetin-mediated mammalian target of rapamycin complex 1 (mTORC1) inhibition, since the phosphorylation levels of p70S6 kinase and 4E-BP1 were decreased in the presence of fisetin. Indeed, fisetin-induced phosphorylated tau degradation was attenuated by chemical inhibitors of the autophagy-lysosome pathway. Together the results indicate that fisetin reduces levels of phosphorylated tau through the autophagy pathway activated by TFEB and Nrf2. Our result suggests fisetin should be evaluated further as a potential preventive and therapeutic drug candidate for AD.

Plasma SUMO1 Protein is Elevated in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common type of dementia in the elderly. The accumulation of amyloid-ß peptides and tau proteins is the major pathogenic event of AD. There is accumulating evidence that both tau and amyloid-ß linked to the small ubiquitin-like modifier (SUMO), which is increased in the brain of AD model mouse. The present study focused on the determination of SUMO1 protein level in AD blood plasma by the ELISA methods. We compared plasma from 80 dementia patients (average age 75.3 y), 89 persons with amnestic mild cognitive impairment (MCI) (average age 73.71 y),and 133 cognitively normal controls (average age 71.97 y). The plasma level of SUMO1 was significantly increased in dementia patients, as compared to control groups. The levels of SUMO1 correlated to decreased Mini-Mental State Examination (r =-0.123, p = 0.029). These results suggest that elevated plasma SUMO1 levels may be associated with AD.

SUMO1 promotes Aß production via the modulation of autophagy.

Autophagy is one of the main mechanisms in the pathophysiology of neurodegenerative disease. The accumulation of autophagic vacuoles (AVs) in affected neurons is responsible for amyloid-ß (Aß) production. Previously, we reported that SUMO1 (small ubiquitin-like modifier 1) increases Aß levels. In this study, we explored the mechanisms underlying this. We investigated whether AV formation is necessary for Aß production by SUMO1. Overexpression of SUMO1 increased autophagic activation, inducing the formation of LC3-II-positive AVs in neuroglioma H4 cells. Consistently, autophagic activation was decreased by the depletion of SUMO1 with small hairpin RNA (shRNA) in H4 cells. The SUMO1-mediated increase in Aß was reduced by the autophagy inhibitors (3-methyladenine or wortmannin) or genetic inhibitors (siRNA targeting ATG5, ATG7, ATG12, or HIF1A), respectively. Accumulation of SUMO1, ATG12, and LC3 was seen in amyloid precursor protein transgenic mice. Our results suggest that SUMO1 accelerates the accumulation of AVs and promotes Aß production, which is a key mechanism for understanding the AV-mediated pathophysiology of Alzheimer disease.

NDP52 associates with phosphorylated tau in brains of an Alzheimer disease mouse model.

We previously showed that NDP52 (also known as calcoco2) plays a role as an autophagic receptor for phosphorylated tau facilitating its clearance via autophagy. Here, we examined the expression and association of NDP52 with autophagy-regulated gene (ATG) proteins including LC3, as well as phosphorylated tau and amyloid-beta (Aß) in brains of an AD mouse model. NDP52 was expressed not only in neurons, but also in microglia and astrocytes. NDP52 co-localized with ATGs and phosphorylated tau as expected since it functions as an autophagy receptor for phosphorylated tau in brain. Compared to wild-type mice, the number of autophagic vesicles (AVs) containing NDP52 in both cortex and hippocampal regions was significantly greater in AD model mice. Moreover, the protein levels of NDP52 and phosphorylated tau together with LC3-II were also significantly increased in AD model mice, reflecting autophagy impairment in the AD mouse model. By contrast, a significant change in p62/SQSTM1 level was not observed in this AD mouse model. NDP52 was also associated with intracellular Aß, but not with the extracellular Aß of amyloid plaques. We conclude that NDP52 is a key autophagy receptor for phosphorylated tau in brain. Further our data provide clear evidence for autophagy impairment in brains of AD mouse model, and thus strategies that result in enhancement of autophagic flux in AD are likely to be beneficial.

Sulforaphane induces autophagy through ERK activation in neuronal cells.

Sulforaphane (SFN), an activator of nuclear factor E2-related factor 2 (Nrf2), has been reported to induce autophagy in several cells. However, little is known about its signaling mechanism of autophagic induction. Here, we provide evidence that SFN induces autophagy with increased levels of LC3-II through extracellular signal-regulated kinase (ERK) activation in neuronal cells. Pretreatment with NAC (N-acetyl-l-cysteine), a well-known antioxidant, completely blocked the SFN-induced increase in LC3-II levels and activation of ERK. Knockdown or overexpression of Nrf2 did not affect autophagy. Together, the results suggest that SFN-mediated generation of reactive oxygen species (ROS) induces autophagy via ERK activation, independent of Nrf2 activity in neuronal cells.

Aging-related Changes in Mouse Serum Glycerophospholipid Profiles.

OBJECTIVES: Metabolic dysfunction is a common hallmark of the aging process and aging-related pathogenesis. Blood metabolites have been used as biomarkers for many diseases, including cancers, complex chronic diseases, and neurodegenerative diseases. METHODS: In order to identify aging-related biomarkers from blood metabolites, we investigated the specific metabolite profiles of mouse sera from 4-month-old and 21-month-old mice by using a combined flow injection analysis-tandem mass spectrometry and liquid chromatography-tandem mass spectrometry. RESULTS: Among the 156 metabolites detected, serum levels of nine individual metabolites were found to vary with aging. Specifically, lysophosphatidylcholine (LPC) acyl (a) C24:0 levels in aged mice were decreased compared to that in young mice, whereas phosphatidylcholine (PC) acyl-alkyl (ae) C38:4, PC ae C40:4, and PC ae C42:1 levels were increased. Three classes of metabolites (amino acids, LPCs, and PCs) differed in intraclass correlation patterns of the individual metabolites between sera from young and aged mice. Additionally, the ratio of LPC a C24:0 to PC ae C38:4 was decreased in the aged mice, whereas the ratio of PC ae C40:4 to LPC a C24:0 was increased, supporting the aging-related metabolic changes of glycerophospholipids. CONCLUSION: The ratios of the individual metabolites PC and LPC could serve as potential biomarkers for aging and aging-related diseases.

SUMO1 modulates Aß generation via BACE1 accumulation.

Accumulation of disease-related proteins is a characteristic event observed in the pathogenesis of neurodegenerative diseases. ß-secretase (BACE)-1, which initiates generation of ß-amyloid (Aß), is increased in the Alzheimer's diseased brain. However, the mechanisms of BACE1 accumulation in Alzheimer's disease are largely unknown. In this report, we found that small ubiquitin-like modifier (SUMO)-1 interacts with the dileucine motif of BACE1 and regulates the level of BACE1 protein. This was proved by the coimmunoprecipitation, and gain or loss of function experiments. Altering 3 SUMO isoforms affects BACE1 protein levels, and consequently results in altered amyloid precursor protein processing and Aß generation. BACE1 levels were increased in response to Aß or apoptosis, but not in cells lacking SUMO1. Aß increased SUMO1 protein levels in rat cortical neurons. Moreover, SUMO1 immunoreactivity was increased in the amyloid precursor protein transgenic mice. Furthermore, the C-terminus fragments of BACE1 containing dileucine motif reduced Aß generation by SUMO1 overexpression. Our study indicates SUMO1 is not only a novel and potent regulator of BACE1 accumulation and Aß generation but also a potential therapeutic target for Alzheimer's disease.

γ-Secretase-dependent cleavage of E-cadherin by staurosporine in breast cancer cells.

E-cadherin is a transmembrane protein that serves as a cell adhesion molecule component of the adherens junction. We previously showed that cadmium induced γ-secretase-dependent E-cadherin cleavage via oxidative stress. In this study, we report that staurosporine (STS)-induced apoptosis induces caspase-2 and/or -8-dependent E-cadherin cleavage. STS increased γ-secretase-dependent cleavage of E-cadherin in breast cancer cells through caspase activation. The ability of the γ-secretase inhibitor DAPT and the caspase inhibitor zVAD-FMK to block E-cadherin cleavage provided support for these results. The cleavage of E-cadherin was blocked by caspase-2 and -8 inhibitors. Immunofluorescence analysis confirmed that, along with the disappearance of E-cadherin staining at the cell surface, the E-cadherin cytoplasmic domain accumulated in the cytosol. In the presence of an inhibitor of γ-secretase or caspase, the cleavage of E-cadherin was partially blocked. Our findings suggest that activation of caspase-2/-8 stimulated the disruption of cadherin-mediated cell-cell contacts in apoptotic cells via γ-secretase activation.

Plasma carbonic anhydrase II protein is elevated in Alzheimer's disease.

Carbonic anhydrase (CA) plays a critical role in pH regulation, long-term synaptic transformation, and is associated with mental retardation, Alzheimer's disease (AD), and Down syndrome. There is accumulating evidence that CAII is increased in AD brain. The present study focused on the determination of CAII protein level in blood plasma samples using immunoblot and ELISA methods. We compared plasma from 91 AD patients (average age 74.8 y), 83 persons with amnestic mild cognitive impairment (MCI) (average age 73.7 y), and 113 cognitively normal controls (average age 70.8 y). The plasma level of CAII was significantly increased in AD patients, as compared to control groups. CAII levels were higher in males than females. There was an age-dependent increase of CAII. These results provide further evidence that changes in CAII level may play a role in the pathogenesis of AD.

Caspases-2 and -8 are involved in the presenilin1/gamma-secretase-dependent cleavage of amyloid precursor protein after the induction of apoptosis.

The presenilin/gamma-secretase protease cleaves many type-I membrane proteins, including the amyloid beta-protein (Abeta) precursor (APP). Previous studies have shown that apoptosis induces alterations in Abeta production in a caspase-dependent manner. Here, we report that staurosporine (STS)-induced apoptosis induces caspase-8 and/or-2-dependent gamma-secretase activation. Blocking of caspase activity with caspase-8 inhibitor z-IETD-fmk, and caspase-2 inhibitor z-VDVAD-fmk reduced Abeta production by STS in H4 cells expressing the Swedish mutant of APP (HSW) or APP-C99 (H4-C99). There was no inhibitory effect of other caspases (-1, -3, -5, -6, -9) on Abeta production by STS. This finding was further supported by evidence that siRNA transfection, depleting caspase-2 or -8 levels, lowered Abeta production in HSW and H4-C99 cells without affecting expression of APP or gamma-secretase complex. In addition, Abeta production by STS was decreased by JNK inhibitors, SP600125. These results suggest that caspase-2 and/or -8 is involved in presenilin/gamma-secretase activation and Abeta production in apoptosis.