g Chul Youn

Activation of PERK Signaling Attenuates Aβ-Mediated ER Stress

Alzheimers disease (AD) is characterized by the deposition of aggregated beta-amyloid (Aβ), which triggers a cellular stress response called the unfolded protein response (UPR). The UPR signaling pathway is a cellular defense system for dealing with the accumulation of misfolded proteins but switches to apoptosis when endoplasmic reticulum (ER) stress is prolonged. ER stress is involved in neurodegenerative diseases including AD, but the molecular mechanisms of ER stress-mediated Aβ neurotoxicity still remain unknown. Here, we show that treatment of Aβ triggers the UPR in the SK-N-SH human neuroblastoma cells. Aβ mediated UPR pathway accompanies the activation of protective pathways such as Grp78/Bip and PERK-eIF2α pathway, as well as the apoptotic pathways of the UPR such as CHOP and caspase-4. Knockdown of PERK enhances Aβ neurotoxicity through reducing the activation of eIF2α and Grp8/Bip in neurons. Salubrinal, an activator of the eIF2α pathway, significantly increased the Grp78/Bip ER chaperone resulted in attenuating caspase-4 dependent apoptosis in Aβ treated neurons. These results indicate that PERK-eIF2α pathway is a potential target for therapeutic applications in neurodegenerative diseases including AD.

The genetics of Alzheimer’s disease

Alzheimer’s disease (AD) is a complex and heterogeneous neurodegenerative disorder, classified as either early onset (under 65 years of age), or late onset (over 65 years of age). Three main genes are involved in early onset AD: amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2). The apolipoprotein E (APOE) E4 allele has been found to be a main risk factor for late-onset Alzheimer’s disease. Additionally, genome-wide association studies (GWASs) have identified several genes that might be potential risk factors for AD, including clusterin (CLU), complement receptor 1 (CR1), phosphatidylinositol binding clathrin assembly protein (PICALM), and sortilin-related receptor (SORL1). Recent studies have discovered additional novel genes that might be involved in late-onset AD, such as triggering receptor expressed on myeloid cells 2 (TREM2) and cluster of differentiation 33 (CD33). Identification of new AD-related genes is important for better understanding of the pathomechanisms leading to neurodegeneration. Since the differential diagnoses of neurodegenerative disorders are difficult, especially in the early stages, genetic testing is essential for diagnostic processes. Next-generation sequencing studies have been successfully used for detecting mutations, monitoring the epigenetic changes, and analyzing transcriptomes. These studies may be a promising approach toward understanding the complete genetic mechanisms of diverse genetic disorders such as AD.

Clinical Characteristics of a Nationwide Hospital-based Registry of Mild-to-Moderate Alzheimer's Disease Patients in Korea: A CREDOS (Clinical Research Center for Dementia of South Korea) Study

With rapid population aging, the socioeconomic burden caused by dementia care is snowballing. Although a few community-based studies of Alzheimers disease (AD) have been performed in Korea, there has never been a nationwide hospital-based study thereof. We aimed to identify the demographics and clinical characteristics of mild-to-moderate AD patients from the Clinical Research Center for Dementia of Korea (CREDOS) registry. A total of 1,786 patients were consecutively included from September 2005 to June 2010. Each patient underwent comprehensive neurological examination, interview for caregivers, laboratory investigations, neuropsychological tests, and brain MRI. The mean age was 74.0 yr and the female percentage 67.0%. The mean period of education was 7.1 yr and the frequency of early-onset AD (< 65 yr old) was 18.8%. Among the vascular risk factors, hypertension (48.9%) and diabetes mellitus (22.3%) were the most frequent. The mean score of the Korean version of Mini-Mental State Examination (K-MMSE) was 19.2 and the mean sum of box scores of Clinical Dementia Rating (CDR-SB) 5.1. Based on the well-structured, nationwide, and hospital-based registry, this study provides the unique clinical characteristics of AD and emphasizes the importance of vascular factors in AD in Korea.

Protective effect of serotonin on 6-hydroxydopamine- and dopamine-induced oxidative damage of brain mitochondria and synaptosomes and PC12 cells.

The present study elucidated the effects of indoleamines (serotonin, melatonin, and tryptophan) on oxidative damage of brain mitochondria and synaptosomes induced either by 6-hydroxydopamine (6-OHDA) or by iron plus ascorbate and on viability loss in dopamine-treated PC12 cells. Serotonin (1-100 microM), melatonin (100 microM), and antioxidant enzymes attenuated the effects of 6-OHDA, iron plus ascorbate, or 1-methyl-4-phenylpyridinium on mitochondrial swelling and membrane potential formation. Serotonin and melatonin decreased the attenuation of synaptosomal Ca(2+) uptake induced by either 6-OHDA alone or iron plus ascorbate. Serotonin and melatonin inhibited the production of reactive oxygen species, formation of malondialdehyde and carbonyls, and thiol oxidation in mitochondria and synaptosomes and decreased degradation of 2-deoxy-D-ribose. Unlike serotonin, melatonin did not reduce the iron plus ascorbate-induced thiol oxidation. Tryptophan decreased thiol oxidation and 2-deoxy-D-ribose degradation but did not inhibit the production of reactive oxygen species and formation of oxidation products in the brain tissues. Serotonin and melatonin attenuated the dopamine-induced viability loss, including apoptosis, in PC12 cells. The results suggest that serotonin may attenuate the oxidative damage of mitochondria and synaptosomes and the dopamine-induced viability loss in PC12 cells by a decomposing action on reactive oxygen species and inhibition of thiol oxidation and shows the effect comparable to melatonin. Serotonin may show a prominent protective effect on the iron-mediated neuronal damage.

Impact of white matter changes on activities of daily living in mild to moderate dementia.

The association between white matter changes and activities of daily living (ADL) in a large, well-defined cohort of patients with mild-to-moderate dementia (either Alzheimer’s disease or subcortical vascular dementia) were investigated. A total of 289 patients were divided into three groups (140 mild, 99 moderate, and 50 severe) depending on the degree of white matter changes as indicated on brain magnetic resonance image scans. Further, we analyzed the three groups’ performances on basic and instrumental ADL. The degree of white matter changes was associated with greater age, hypertension, previous history of stroke, higher Hachinski Ischemic Score, worse global cognitive and functional status, and an increased impairment of basic ADL and instrumental ADL. The increased impairment with regard to the severe group’s performance on both the basic and instrumental ADL remained significant after adjustment for age and hypertension. Tasks involving physical activities were most significant. This was the first study investigating the association between white matter changes and ADL in a large, well-defined dementia cohort. The present study suggests that severe white matter changes may be associated with higher impairment on both basic and instrumental ADL.

Protective effect of boldine on dopamine-induced membrane permeability transition in brain mitochondria and viability loss in PC12 cells.

Boldine ([S]-2,9-dihydroxy-1,10-dimethoxyaporphine) has been shown to exert antioxidant and anti-inflammatory effects. The present study elucidated the protective effect of boldine on catecholamine-induced membrane permeability transition in brain mitochondria and viability loss in PC12 cells. Dopamine (200 microM) and 6-hydroxydopamine (6-OHDA, 100 microM) attenuated Ca(2+) and succinate-induced mitochondrial swelling and membrane potential formation. Boldine (10-100 microM) and 10 microg/mL of superoxide dismutase (SOD) or catalase reduced the effect of catecholamine oxidation on brain mitochondria. Boldine, SOD, and catalase decreased catecholamine-induced mitochondrial cytochrome c release. Antioxidant enzymes attenuated the depressant effect of catecholamines on mitochondrial electron flow, whereas boldine did not reduce it. Boldine inhibited the catecholamine-induced decrease in thioredoxin reductase activity and the increase in thiol oxidation in mitochondria. It also showed a scavenging action on hydrogen peroxide and hydroxyl radicals and decreased the formation of melanin from dopamine. Boldine and antioxidant enzymes decreased the dopamine-induced cell death, including apoptosis, in PC12 cells. The results suggest that boldine may attenuate the catecholamine oxidation-induced brain mitochondrial dysfunction and decrease the dopamine-induced death of PC12 cells through a scavenging action on reactive oxygen species and inhibition of melanin formation and thiol oxidation.

Effects of Medial Temporal Atrophy and White Matter Hyperintensities on the Cognitive Functions in Patients with Alzheimer’s Disease

Aims: We conducted this study to investigate the independent association of medial temporal atrophy (MTA) and white matter hyperintensities (WMH) with cognitive impairments of Alzheimer’s disease (AD) patients and the interaction between MTA and WMH. Methods: From 13 centers, a total of 216 AD patients were consecutively recruited and their MTA and WMH were visually rated. We evaluated the association of MTA and WMH with the various cognitive domains, and the interaction between MTA and WMH. Results: MTA independently correlated with scores of the Mini-Mental State Examination (MMSE), Clinical Dementia Rating scale (CDR), delayed recalls of the Seoul Verbal Learning Test (SVLT), the Boston Naming Test (BNT), and Word Fluency. WMH independently correlated with MMSE, CDR, Digit Span, and Stroop word reading, but not with delayed recall. There were interactions of WMH and MTA on CDR (p = 0.004), SVLT (p = 0.023), BNT (p = 0.002) and the semantic Word Fluency (p = 0.007). Conclusion: MTA and WMH independently affected cognitive deficits in AD patients, with somewhat different patterns where MTA was associated mostly with memory and language, while WMH were associated with attention and frontal executive functions. This study also showed interactions between MTA and WMH on some cognitive deficits and dementia severity, suggesting that they synergistically contribute to cognitive impairment in AD.

Intracranial Internal Carotid Artery Calcification: A Representative for Cerebral Artery Calcification and Association with White Matter Hyperintensities

Background: Our aim was to investigate the distribution pattern of cerebral artery calcification and its association with white matter hyperintensities (WMH). Methods: We identified 159 consecutive patients with acute ischemic stroke. Calcifications of cerebral arteries and WMH were graded. Results: Cerebral artery calcification was found in 137 patients (86.2%). The intracranial internal carotid artery (I-ICA) was the most frequently affected artery with calcification (76.7%) and moderate-to-severe calcification (38.1%). Spearman’s rank test revealed that the grade of I-ICA calcification was correlated with those of periventricular WMH (r = 0.417, p < 0.001) and deep WMH (r = 0.388, p < 0.001). The adjusted ORs of I-ICA were 2.62 (p <0.05) for periventricular WMH and 3.25 (p <0.05) for deep WMH. Conclusions: Cerebral artery calcification is common in patients with ischemic stroke. I-ICA is the most frequently and most severely affected cerebral artery and its calcification is associated with WMH.

Serum Vitamin D Status as a Predictor of Prognosis in Patients with Acute Ischemic Stroke

Background: Low 25-hydroxyvitamin D (25(OH)D) concentrations have been shown to predict risk of cardiovascular disease and all-cause mortality. Although the prevalence of 25(OH)D deficiency is high in patients with acute stroke, the prognostic value of 25(OH)D in stroke has not been clearly established. The purpose of this study was to determine whether the baseline serum 25(OH)D level was associated with the functional outcome in patients with acute ischemic stroke. Methods: From June 2011 to January 2014, consecutive patients with acute ischemic stroke within 7 days of symptom onset were enrolled in this study from a prospectively maintained stroke registry. Serum 25(OH)D level was measured at admission. Clinical and laboratory data including stroke severity using the National Institute of Health Stroke Scale (NIHSS) score were collected during admission, and the functional outcome at 3 months was assessed by modified Rankin scale (mRS). The association between the baseline 25(OH)D level and a good functional outcome (mRS 0-2) at 3 months was analyzed by multiple logistic regression models. Results: A total of 818 patients were enrolled in this study. Mean age was 66.2 (±12.9) years, and 40.5% were female. The mean 25(OH)D level was 47.2 ± 31.7 nmol/l, and the majority of patients met vitamin D deficient status (<50 nmol/l; 68.8%), while an optimal vitamin D level (≥75 nmol/l) was present in only 13.6% of the patients, and 436 (53.3%) patients showed good functional outcome at 3 months. Serum 25(OH)D levels in patients with good outcomes were significantly higher than those with poor outcome (50.2 ± 32.7 vs. 43.9 ± 30.0 nmol/l, p = 0.007). The 3-month functional outcome was significantly associated with month-specific 25(OH)D quartiles in multivariable logistic regression analysis. After adjustment for age and sex, the highest 25(OH)D quartile group had higher tendency for good functional outcome at 3 months (odds ratio (OR) = 1.68, 95% confidence interval (CI) = 1.13-2.51). After fully adjusting for other potential confounders, such as stroke severity and vascular risk factors, the association was further strengthened with an OR (95% CI) of 1.90 (1.14-3.16). Other factors associated with good functional outcome in multivariable analysis were younger age, lower initial NIHSS score and absence of diabetes. Conclusions: This study suggests that serum 25(OH)D level is an independent predictor of functional outcome in patients with acute ischemic stroke. Further studies are required to determine whether vitamin D supplementation could improve functional outcome in patients with ischemic stroke.

Voxel-based morphometric study of brain volume changes in patients with Alzheimer’s disease assessed according to the Clinical Dementia Rating score

We evaluated the volume reduction of gray matter (GM) and white matter (WM) in patients with an Alzheimers disease (AD) assessment based on the Clinical Dementia Rating (CDR) score. Patients with AD (n=61), with no subcortical WM ischemia, and healthy control patients (n=33) underwent T1-weighted spoiled gradient echo sequences, which were analyzed using voxel-based morphometry. Global GM volume reduction was observed in patients with a CDR score of 1 or a CDR score of 2, and WM volume reduction was observed in patients with a CDR score of 2. Regional GM volume reduction was found in the right inferior frontal gyrus, bilateral dorso-lateral and medial temporal lobes; WM volume reduction was found in the bilateral temporal subcortex (family-wise error, p<0.01). A CDR score of 0.5 was associated with volume reduction in the left olfactory gyrus. The peak z-score and spatial extent of volume reduction increased with increasing CDR score and were higher on the left side. GM volume reduction increased with increasing CDR scores and suggests a possible pathomechanism of AD.