Apolipoprotein E and clusterin inhibit the early phase of amyloid-β aggregation in an in vitro model of cerebral amyloid angiopathy

Sporadic cerebral amyloid angiopathy (CAA) is characterized by cerebrovascular amyloid-β (Aβ) deposition, which leads to lobar hemorrhage and dementia. Biological molecules affecting the development of CAA have not been fully characterized. In this study, we performed proteome analysis of biopsied leptomeningeal and cortical vessels obtained from 6 CAA patients and 5 non-CAA patients who underwent surgery for large lobar hemorrhages. We found that 6 proteins, including Aβ, apolipoprotein E (apoE), clusterin (CLU), albumin, complement C4 and vitronectin were significantly upregulated in the vessels of CAA patients as compared to non-CAA patients. ApoE and CLU were found in all CAA patients. We next examined the effects of apoE and CLU on the early phase of Aβ aggregation, using a simple yet powerful in vitro model of CAA, which recapitulates the intramural periarterial drainage pathway model. We found that physiological concentrations of apoE and CLU delayed the initiation time of amyloid growth kinetics in a concentration-dependent manner. These data indicate that apoE and CLU may act as extracellular chaperones to inhibit Aβ amyloid deposition in CAA

Hypertension treatment status and ultrasonic cardiography findings in temporary housing residents after the Kumamoto earthquake: a cross-sectional study

Background: We aimed to investigate and report the relationship between hypertension treatment status and cardiac functions among temporary housing residents after the Kumamoto earthquake. Material and methods: Ultrasonic cardiography examinations were conducted for 56 residents at temporary housing complexes in Minami Aso village in Kumamoto Prefecture in December 2016. The subjects were divided into the following three groups according to the incidence of hypertension and the antihypertensive treatment status: normal (without hypertension), treated, and untreated. Subsequently, their cardiac functions were compared. Results: Age and BMI were found to be positive predictors for hypertension. Moreover, age, LAVI, and LVMI tended to be higher in the untreated group than in the treated group. Moderate or severe mitral regurgitation was significantly more common in the untreated group than in the treated group. Conclusions: Controlling blood pressure may help to prevent new cardiac diseases (e.g., valve regurgitation) among survivors after a major disaster. In addition, for survivors who are  severely affected by psychological stress, improving the mental stress support system may be an effective measure to reduce health problems

Deep-vein thrombosis detection rates and consideration of the living environment in a tsunami disaster area during the disaster reconstruction phase: A cross-sectional study

Introduction: Tsunami victims of the Great East Japan Earthquake were screened for deep-vein thrombosis(DVT) in order to compare the DVT incidence rates between temporary and non-temporary housing residentgroups. Material and methods: Lower extremity venous ultrasonography was performed on 290 subjects (64 menand 226 women; mean age = 71.9 ± 7.9 years) at 44 months after the disaster. All subjects completedquestionnaires to gather information about their background factors which included the Kessler PsychologicalDistress Scale: K6. Results: The DVT detection rate was 10.7% in the temporary group. In the non-temporary group, it was 11.3%among the subjects who previously lived in temporary housing. For the subjects who were living in their own homes it was 9.2%. Psychological distress levels measured by K6 were significantly higher in the temporary housinggroup than in the non-temporary housing group. The multivariate analysis showed that the background factorassociated with DVT risk was SV (soleal vein) dilatation in all subjects as well as in the non-temporary housinggroup, while hypertension and use of sleeping pills were found to be the factors in the temporary housing group. Conclusions: DVT detection rates were similar between the temporary and non-temporary housing groups,and were higher than that in the Japanese general population. The psychological distress level of the tsunamivictims measured by K6 was also higher in the temporary housing group than in the non-temporary housinggroup. It is necessary to establish a long-term and awareness-raising disaster victim support system

Decreased circulating branched-chain amino acids are associated with development of Alzheimer’s disease in elderly individuals with mild cognitive impairment

BackgroundNutritional epidemiology has shown that inadequate dietary protein intake is associated with poor brain function in the elderly population. The plasma free amino acid (PFAA) profile reflects nutritional status and may have the potential to predict future changes in cognitive function. Here, we report the results of a 2-year interim analysis of a 3-year longitudinal study following mild cognitive impairment (MCI) participants.MethodIn a multicenter prospective cohort design, MCI participants were recruited, and fasting plasma samples were collected. Based on clinical assessment of cognitive function up to 2 years after blood collection, MCI participants were divided into two groups: remained with MCI or reverted to cognitively normal (“MCI-stable,” N = 87) and converted to Alzheimer’s disease (AD) (“AD-convert,” N = 68). The baseline PFAA profile was compared between the two groups. Stratified analysis based on apolipoprotein E ε4 (APOE ε4) allele possession was also conducted.ResultsPlasma concentrations of all nine essential amino acids (EAAs) were lower in the AD-convert group. Among EAAs, three branched-chain amino acids (BCAAs), valine, leucine and isoleucine, and histidine (His) exhibited significant differences even in the logistic regression model adjusted for potential confounding factors such as age, sex, body mass index (BMI), and APOE ε4 possession (p < 0.05). In the stratified analysis, differences in plasma concentrations of these four EAAs were more pronounced in the APOE ε4-negative group.ConclusionThe PFAA profile, especially decreases in BCAAs and His, is associated with development of AD in MCI participants, and the difference was larger in the APOE ε4-negative population, suggesting that the PFAA profile is an independent risk indicator for AD development. Measuring the PFAA profile may have importance in assessing the risk of AD conversion in the MCI population, possibly reflecting nutritional status.Clinical trial registration[https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000025322], identifier [UMIN000021965]

Autophagy and Tau Protein

Neurofibrillary tangles, which consist of highly phosphorylated tau protein, and senile plaques (SPs) are pathological hallmarks of Alzheimer’s disease (AD). In swollen axons, many autophagic vacuoles are observed around SP in the AD brain. This suggests that autophagy function is disturbed in AD. We used a neuronal cellular model of tauopathy (M1C cells), which harbors wild type tau (4R0N), to assess the effects of the lysosomotrophic agent NH4Cl, and autophagy inhibitors chloroquine and 3 methyladenine (3MA). It was found that chloroquine, NH4Cl and 3MA markedly increased tau accumulation. Thus, autophagy lysosomal system disturbances disturbed the degradation mechanisms of tau protein. Other studies also revealed that tau protein, including aggregated tau, is degraded via the autophagy lysosome system. Phosphorylated and C terminal truncated tau were also reported to disturb autophagy function. As a therapeutic strategy, autophagy upregulation was suggested. Thus far, as autophagy modulators, rapamycin, mTOCR1 inhibitor and its analogues, lithium, metformin, clonidine, curcumin, nicotinamide, bexaroten, and torehalose have been proposed. As a therapeutic strategy, autophagic modulation may be the next target of AD therapeutics

Concentration-dependent Effects of Proteasomal Inhibition on tau Processing in a Cellular Model of Tauopathy

Tauopathies are characterized by accumulation of filamentous tau aggregates. These aggregates can be recapitulated in transfectant M1C overproducing wild-type human brain tau 4R0N via the tetracycline off (TetOff) inducible expression mechanism. To determine the contribution of proteasomes to tau degradation and aggregation, we exposed M1C cells to epoxomicin (Epx; 2-50 nM) or MG132 (0.5 μM) on the 3rd or 4th day of a 5-day TetOff induction and demonstrated a reduction of proteasomal activity. Cultures treated with 2 nM Exp showed accumulation of full-length tau without affecting ubiquitin and β-catenin immunoblotting profiles. In contrast, cells treated with 10, 50 nM Epx or MG132 displayed changes in ubiquitin or β-catenin immunoblotting profiles and extensive tau degradation/truncation. The increase of tau degradation/truncation was accompanied with accumulation of oligomers and sarkosyl-insoluble aggregates of tau, augmented thioflavin-binding and activation of caspases and calpains. Truncated, oligomeric and sarkosyl-insoluble tau derivatives appeared with caspase-specific cleavage and their production was diminished when pretreated with a pan-caspase inhibitor. The results demonstrate (i) a dose-dependent, opposite effect of proteasome inhibition on tau processing, (ii) the participation of proteasome-dependent, ubiquitination-independent mechanisms in tau degradation and aggregation, and (iii) the promotion of tau aggregation by caspase-mediated tau degradation/truncation