High Fat Diet Enhances ß-Site Cleavage of Amyloid Precursor Protein (APP) via Promoting ß-Site APP Cleaving Enzyme 1/Adaptor Protein 2/Clathrin Complex Formation.

Obesity and type 2 diabetes are risk factors of Alzheimer's disease (AD). We reported that a high fat diet (HFD) promotes amyloid precursor protein (APP) cleavage by ß-site APP cleaving enzyme 1 (BACE1) without increasing BACE1 levels in APP transgenic mice. However, the detailed mechanism had remained unclear. Here we demonstrate that HFD promotes BACE1/Adaptor protein-2 (AP-2)/clathrin complex formation by increasing AP-2 levels in APP transgenic mice. In Swedish APP overexpressing Chinese hamster ovary (CHO) cells as well as in SH-SY5Y cells, overexpression of AP-2 promoted the formation of BACE1/AP-2/clathrin complex, increasing the level of the soluble form of APP ß (sAPPß). On the other hand, mutant D495R BACE1, which inhibits formation of this trimeric complex, was shown to decrease the level of sAPPß. Overexpression of AP-2 promoted the internalization of BACE1 from the cell surface, thus reducing the cell surface BACE1 level. As such, we concluded that HFD may induce the formation of the BACE1/AP-2/clathrin complex, which is followed by its transport of BACE1 from the cell surface to the intracellular compartments. These events might be associated with the enhancement of ß-site cleavage of APP in APP transgenic mice. Here we present evidence that HFD, by regulation of subcellular trafficking of BACE1, promotes APP cleavage.

[Supervised administration of Alzheimer's patients using information communication technology].

Drug adherence is central to the treatment of dementia, which might reduce compliance due to memory loss, particularly among home-based patients with dementia. In order to improve drug adherence, we suggest the efficient and effective supervised administration by use of information communication technology(ICT). ICT makes face-to-face real-time communication possible, and it also enables picture sharing. Therefore, it might be useful to apply ICT to controlling and supervising medication for patients with dementia to improve drug adherence. Accordingly, we enrolled patients who were supposed to take a newly prescribed anti-dementia patch containing the choline esterase inhibitor rivastigmine(Rivastach®)and investigated the effect of ICT-based intervention for drug adherence, emotional change, and cognitive change, utilizing Skype, a free communication software program. Scheduled Skype interventions increased drug adherence ratio, levels of subjective satisfaction, and instrumental activities of daily living(IADL). Furthermore, we can provide patients and their caregivers with a feeling of safety through regular bidirectional communication, as patients can easily consult medical staff regarding the adverse effects of newly prescribed drugs. Instead of frequent visits to their primary physicians, ICT-based communications can be used as a substitute for supervision of medication, given the availability of the telecommunication system. By directly connecting the medical institution to the home, we expect that this ICT-based system will expand into the geriatric care field, including the care of elderly individuals living alone.

[At-home music therapy intervention using video phone (Skype) for elderly people with dementia].

There are various nonpharmacological therapies available for elderly people with dementia, and these can improve quality of life and the behavioral and psychological symptoms of dementia (BPSD) that appear throughout the progression of the disease. Since a substantial number of effects have been reported for music therapy, we focused on this nonpharmacological intervention. Generally, musical therapy is provided collectively in facilities. However, the music used in this context may not consider the preferences and music abilities of each person. Therefore, in this study we created made-to-order music CDs that accounted for each participant's musical preferences and abilities. Utilizing the CDs, we conducted an intervention study of music therapy using a video phone (Skype) that elderly people with dementia can use at home. An advantage of conducting music therapy for individuals with dementia using a video phone is that those who have difficulty going to the hospital or participating in dementia-related therapy groups can participate in therapy in a familiar place. The results of this intervention showed that participants demonstrated signs of improvement as measured by the smile degree(Smile scan)and Behavior Pathology in Alzheimer's Disease (BEHAVE-AD) scale.

Continuation of exercise is necessary to inhibit high fat diet-induced ß-amyloid deposition and memory deficit in amyloid precursor protein transgenic mice.

High fat diet (HFD) is prevalent in many modern societies and HFD-induced metabolic condition is a growing concern worldwide. It has been previously reported that HFD clearly worsens cognitive function in amyloid precursor protein (APP) transgenic mice. On the other hand, we have demonstrated that voluntary exercise in an enriched environment is an effective intervention to rescue HFD-induced ß-amyloid (Aß) deposition and memory deficit. However, it had been unclear whether consumption of HFD after exercising abolished the beneficial effect of exercise on the inhibition of Alzheimer's disease (AD) pathology. To examine this question, we exposed wild type (WT) and APP mice fed with HFD to exercise conditions at different time periods. In our previous experiment, we gave HFD to mice for 20 weeks and subjected them to exercise during weeks 10-20. In the present study, mice were subjected to exercise conditions during weeks 0-10 or weeks 5-15 while being on HFD. Interestingly, we found that the effect of exercise during weeks 0-10 or weeks 5-15 on memory function was not abolished in WT mice even if they kept having HFD after finishing exercise. However, in APP transgenic mice, HFD clearly disrupted the effect of exercise during weeks 0-10 or weeks 5-15 on memory function. Importantly, we observed that the level of Aß oligomer was significantly elevated in the APP mice that exercised during weeks 0-10: this might have been caused by the up-regulation of Aß production. These results provide solid evidence that continuation of exercise is necessary to rescue HFD-induced aggravation of cognitive decline in the pathological setting of AD.

Copper enhances APP dimerization and promotes Aß production.

Alzheimer's disease (AD) is characterized by the deposition of amyloid-ß (Aß) plaques, senile plaque. The Aß peptide is cleaved from amyloid precursor protein (APP) by ß-secretase and γ-secretase. Until now, many literatures have documented that the high concentration of copper is present in Aß plaques and enhances aggregation of. The APP copper binding domain (CuBD) is located in the N-terminal next to the growth factor-like domain that gets involved in APP homodimerization. Importantly, dimerization of APP has profound effect on Aß production. We investigated whether copper alters the state of APP dimerization and how it affects APP metabolism. Here, we demonstrate that copper enhanced APP dimerization and increased extracellular release of Aß. Moreover, copper chelator, D-penicillamine, suppressed APP dimerization and decreased extracellular release of Aß. These results suggest that the action of copper may be profoundly associated with the pathway of Aß production in AD pathogenesis.

[Support for the medication monitoring of patients with alzheimer's dementia by the interactive care system using IT].

In our laboratory, we draw up research aims to improve medication compliance in patients with dementia by video phone, and we have intervened in the cases of 3 patients to date. In this study, we focused on patients who are using a rivastigmine patch for Alzheimer' disease, which can be confirmed by video phone, to examine its efficacy. Specifically, by monitoring the effects of the treatment, skin side effects, of skin and usability for patients and caregivers, we monitor the dosing schedule to prevent interruption of self-medication, with the aim of improving compliance and treatment efficacy. We also consider methods of intervention for increasing the persistence rate of the rivastigmine patch and quality of life(QOL)by using the effectiveness of the video phone to focus on the symptoms of skin side effects. In addition, we examine the interventions that reduce the care burden and anxiety of caregivers by listening during the regular intervention.

Exercise is more effective than diet control in preventing high fat diet-induced ß-amyloid deposition and memory deficit in amyloid precursor protein transgenic mice.

Accumulating evidence suggests that some dietary patterns, specifically high fat diet (HFD), increase the risk of developing sporadic Alzheimer disease (AD). Thus, interventions targeting HFD-induced metabolic dysfunctions may be effective in preventing the development of AD. We previously demonstrated that amyloid precursor protein (APP)-overexpressing transgenic mice fed HFD showed worsening of cognitive function when compared with control APP mice on normal diet. Moreover, we reported that voluntary exercise ameliorates HFD-induced memory impairment and ß-amyloid (Aß) deposition. In the present study, we conducted diet control to ameliorate the metabolic abnormality caused by HFD on APP transgenic mice and compared the effect of diet control on cognitive function with that of voluntary exercise as well as that of combined (diet control plus exercise) treatment. Surprisingly, we found that exercise was more effective than diet control, although both exercise and diet control ameliorated HFD-induced memory deficit and Aß deposition. The production of Aß was not different between the exercise- and the diet control-treated mice. On the other hand, exercise specifically strengthened the activity of neprilysin, the Aß-degrading enzyme, the level of which was significantly correlated with that of deposited Aß in our mice. Notably, the effect of the combination treatment (exercise and diet control) on memory and amyloid pathology was not significantly different from that of exercise alone. These studies provide solid evidence that exercise is a useful intervention to rescue HFD-induced aggravation of cognitive decline in transgenic model mice of AD.

Gain of function by phosphorylation in Presenilin 1-mediated regulation of insulin signaling.

We have recently reported that Presenilin 1 (PS1), a causative gene of familial Alzheimer disease (AD), down-regulates the expression level of insulin receptor (IR) as well as its signaling through a γ-secretase-independent pathway. PS1 is phosphorylated by glycogen synthase kinase 3 ß at the serine 353 and 357 residues. The main purpose of the present study was to clarify the effect of PS1 phosphorylation on IR/insulin signaling. Here, we demonstrate that the pseudo-phosphorylation mutant of PS1 inhibited IR transcription and reduced IR expression compared with wild-type PS1. Importantly, there was a decrease in expression of IR in AD brains, and the phosphorylation ratio of PS1 was negatively correlated with IR level in human brain samples. In the data from mouse models of AD, IR reduction was not observed at the pre-Aß deposition stage but became apparent in that of post-Aß deposition. Together with our previous reports, these results suggest that phosphorylated PS1 can promote the down-regulation of insulin signaling, which may be a positive feed-forward mechanism inhibiting insulin signaling. As insulin resistance is reported to be a risk factor for sporadic AD, this PS1-mediated regulatory mechanism of brain insulin signaling may be causally associated with AD pathology.

Environmental enrichment ameliorated high-fat diet-induced Aß deposition and memory deficit in APP transgenic mice.

The pathogenesis of Alzheimer's disease (AD) is tightly associated with metabolic dysfunctions. In particular, a potential link between type 2 diabetes (T2DM) and AD has been suggested epidemiologically, clinically, and experimentally, and some studies have suggested that exercise or dietary intervention reduces risk of cognitive decline. However, there is little solid molecular evidence for the effective intervention of metabolic dysfunctions for prevention of AD. In the present study, we established the AD model mice with diabetic conditions through high-fat diet (HFD) to examine the effect of environmental enrichment (EE) on HFD-induced AD pathophysiology. Here, we demonstrated that HFD markedly deteriorated memory impairment and increased ß-amyloid (Aß) oligomers as well as Aß deposition in amyloid precursor protein (APP) transgenic mice, which was reversed by exposure to an enriched environment for 10 weeks, despite the continuation of HFD. These studies provide solid evidence that EE is a useful intervention to ameliorate behavioral changes and AD pathology in HFD-induced aggravation of AD symptoms in APP transgenic mice.

[The effect of telecommunication(with Skype)to improve a cognitive function for elderly patients with dementia and to reduce a care burden for their care givers].

We conducted an intervention study to clarify how effectively videophone(Skype)was used in the communication for elderly patients with dementia being cared at home and their caregivers. For a period of 12 weeks, a patient-caregiver pair(n =8)communicated with a nurse via computer for 30 minutes once a week. The patient and caregiver worked as a pair. Before and after 12-week study period started, the intervention and control group(n=8)patients were assessed on cognitive scale(HDS-R), ADL, care burden scale(J-ZBI_8)and hours of sleep for caregivers. The result on the 12th week showed a significant improvement in hours of sleep on the intervention group of caregivers, and signs of improvement on the intervention group of patients in HDS-R. According to a questionnaire survey for caregivers, many of them said that a videophone communication was a pleasant experience for the family, and it is also useful for information gathering. Therefore, we think that the videophone communication is useful for a cognitive rehab work and giving good feelings for the patient. It also gives a good satisfaction for the family. Furthermore, a patient who had an intervention for 3 times in 2 years showed a sign of improvements in the cognitive function and care burden scale during the intervention period. However, the score dropped for several months. Therefore, it is important that a continuous intervention is necessary.

[The effect of videophone system for diabetic homecare patients on glycemic control].

It is imperative to develop a novel care approach and low-cost health care system for diabetic patients.Therefore, we conducted an intervention study to clarify how effectively a videophone system could be used in the life style guidance focusing on diet for the diabetic patients cared at home.For the period of 3 months, diabetic patients were communicated with a medical professional staff bi-directionally through a videophone-based communication system for 30 minutes once a week.During the 30-minute intervention, the medical staff checked the list with the change in weight, drug adherence and an exercise habit.We encouraged a diabetic patient to eat properly based on the diet record.The 3-month intervention program resulted in a significant decrease in BW(p<0.001 ), BMI(p<0.001 ), and the average HbA1c level(p<0.005 ).In conclusion, we showed a 3-month intensive communication result using a multimodal videophone system, which revealed a significant decrease in the body weight, BMI and the average HbA1c level.This once a week ICT communication might be useful as an auxiliary therapy to help change a bad daily habit to a good daily habit for a diabetic homecare patient.

N-cadherin enhances APP dimerization at the extracellular domain and modulates Aß production.

Sequential processing of amyloid precursor protein (APP) by ß- and γ-secretase leads to the generation of amyloid-ß (Aß) peptides, which plays a central role in Alzheimer's disease pathogenesis. APP is capable of forming a homodimer through its extracellular domain as well as transmembrane GXXXG motifs. A number of reports have shown that dimerization of APP modulates Aß production. On the other hand, we have previously reported that N-cadherin-based synaptic contact is tightly linked to Aß production. In the present report, we investigated the effect of N-cadherin expression on APP dimerization and metabolism. Here, we demonstrate that N-cadherin expression facilitates cis-dimerization of APP. Moreover, N-cadherin expression led to increased production of Aß as well as soluble APPß, indicating that ß-secretase-mediated cleavage of APP is enhanced. Interestingly, N-cadherin expression affected neither dimerization of C99 nor Aß production from C99, suggesting that the effect of N-cadherin on APP metabolism is mediated through APP extracellular domain. We confirmed that N-cadherin enhances APP dimerization by a novel luciferase-complementation assay, which could be a platform for drug screening on a high-throughput basis. Taken together, our results suggest that modulation of APP dimerization state could be one of mechanisms, which links synaptic contact and Aß production.

Presenilin regulates insulin signaling via a gamma-secretase-independent mechanism.

Presenilin (PS), a causative molecule of familial Alzheimer disease, acts as a crucial component of the γ-secretase complex, which is required to cleave type I transmembrane proteins such as amyloid precursor protein and Notch. However, it also functions through γ-secretase-independent pathways. Recent reports suggested that PS could regulate the expression level of cell surface receptors, including the PDGF and EGF receptors, followed by modulating their downstream pathways via γ-secretase-independent mechanisms. The main purpose of this study was to clarify the effect of PS on expression of the insulin receptor (IR) as well as on insulin signaling. Here, we demonstrate that PS inhibited IR transcription and reduced IR expression, and this was followed by down-regulation of insulin signaling. Moreover, we suggest that neither γ-secretase activity nor Wnt/ß-catenin signaling can reduce the expression of IR, but a PS-mediated increase in the intracellular Ca(2+) level can be associated with it. These results clearly indicate that PS can functionally regulate insulin signaling by controlling IR expression.

N-cadherin regulates p38 MAPK signaling via association with JNK-associated leucine zipper protein: implications for neurodegeneration in Alzheimer disease.

Synaptic loss, which strongly correlates with the decline of cognitive function, is one of the pathological hallmarks of Alzheimer disease. N-cadherin is a cell adhesion molecule essential for synaptic contact and is involved in the intracellular signaling pathway at the synapse. Here we report that the functional disruption of N-cadherin-mediated cell contact activated p38 MAPK in murine primary neurons, followed by neuronal death. We further observed that treatment with Aß(42) decreased cellular N-cadherin expression through NMDA receptors accompanied by increased phosphorylation of both p38 MAPK and Tau in murine primary neurons. Moreover, expression levels of phosphorylated p38 MAPK were negatively correlated with that of N-cadherin in human brains. Proteomic analysis of human brains identified a novel interaction between N-cadherin and JNK-associated leucine zipper protein (JLP), a scaffolding protein involved in the p38 MAPK signaling pathway. We demonstrated that N-cadherin expression had an inhibitory effect on JLP-mediated p38 MAPK signal activation by decreasing the interaction between JLP and p38 MAPK in COS7 cells. Also, this study demonstrated a novel physical and functional association between N-cadherin and p38 MAPK and suggested neuroprotective roles of cadherin-based synaptic contact. The dissociation of N-cadherin-mediated synaptic contact by Aß may underlie the pathological basis of neurodegeneration such as neuronal death, synaptic loss, and Tau phosphorylation in Alzheimer disease brain.

Insulin regulates Presenilin 1 localization via PI3K/Akt signaling.

Recently, insulin signaling has been highlighted in the pathology of Alzheimer's disease (AD). Although the association between insulin signaling and Tau pathology has been investigated in several studies, the interaction between insulin signaling and Presenilin 1 (PS1), a key molecule of amyloid beta (Abeta) pathology, has not been elucidated so far. In this study, we demonstrated that insulin inhibited PS1 phosphorylation at serine residues (serine 353, 357) via phosphatidylinositol 3-kinase (PI3K)/Akt signal pathway and strengthened the trimeric complex of PS1/N-cadherin/beta-catenin, consequently relocalizing PS1 to the cell surface. Since our recent report suggests that PS1/N-cadherin/beta-catenin complex regulates Abeta production, it is likely that insulin signaling affects Abeta pathology by regulating PS1 localization.

Calcium dependence of the priming, activation and inactivation of ryanodine receptors in frog motor nerve terminals.

We studied the effects of varying extracellular Ca(2+) ([Ca(2+) ](o) ) and Ca(2+) channel density and intracellular loading of Ca(2+) chelators on stimulation-induced rises in intracellular Ca(2+) ([Ca(2+) ](i) ) in frog motor nerve terminals with Ca(2+) imaging. The slowly waxing and waning components of rises in [Ca(2+) ](i) induced by repetitive tetani were suppressed by blockers of Ca(2+) pumps of the endoplasmic reticulum (thapsigargin and cyclopiazonic acid) and a blocker of ryanodine receptors [8-(N,N-diethylamino)octyl 3,4,5-trimethoxybenzoate hydrochloride] without affecting the initial quickly-rising component, thus reflecting the priming (and then subsequent rapid activation) and inactivation phases of Ca(2+) -induced Ca(2+) release (CICR) from the endoplasmic reticulum. A short tetanus-induced rise in [Ca(2+) ](i) was proportional to [Ca(2+) ](o) , whereas the component of CICR was non-linearly related to [Ca(2+) ](o) with saturation at 0.9 mm. The progressive blockade of Ca(2+) channels by ω-conotoxin GVIA caused proportional decreases in CICR and short tetanus-induced [Ca(2+) ](i) rises. Intracellular loading of BAPTA and EGTA reduced the magnitude of CICR as well as short tetanus-induced rises in [Ca(2+) ](i) with a greater effect of BAPTA than EGTA on CICR. The time to peak and the half decay time of CICR were prolonged by a low [Ca(2+) ](o) or Ca(2+) channel blocker or [Ca(2+) ](i) chelators. These results suggest that ryanodine receptors sense the high [Ca(2+) ](i) transient following single action potentials for triggering CICR, whereas the priming and inactivation processes of CICR sense a slower, persisting rise in [Ca(2+) ](i) during and after action potential trains. A model is presented that includes CICR activation in elementary units.

[The Support System for Diabetic Patients at Home with Bi-Directional IT Communication].

The present study analyzed the effects of bi-directional IT communication on the purpose of preventing diabetes progression and to reduce a caregiver burden. Diabetic patients were informed of the nature and purpose of the study before giving their voluntary consents to participate in the study. For the period of 12 weeks, a diabetic patient and his caregiver were communicated with a nurse through the TV telephone for 30 minutes once a week. Medical staff checked the list of weight change, compliance check, exercise habit, and attached pictures of the plate with a diabetic patient through the TV telephone in real time. We encouraged a diabetic patient to eat properly based on the diet record. The 12-week TV telephone communication resulted in the body weight decrease and HbA1c. There was a consciousness change about their daily eating habit. In the present study, the 12-week TV telephone communication once a week might be useful as an auxiliary therapy for changing a bad daily habit to a good daily habit for a diabetic patient at home.

[Blogging is an effective way to reduce a stress for caregivers who are involved in caring dementia patients at home--the result from the questionnaire survey].

We sent out questionnaires to examine how caregivers, who are involved in caring home dementia patients, effectively reduce their stresses by blogging. A total of 39 caregivers(13 males and 26 females)filled out a questionnaire(write-in free descriptive type)by E-mail. What was it that you gained from blogging to reduce a stress from the work ? The responses to that question were: (1) social support, (2) coping with stress, and (3) perception of the event. These answers appeared to be agreed with the crisis theory of Aguilera. In the situation where a lot of stresses were involved, it was clear that blogging was an effective way to reduce a stress for caregivers who were involved in caring dementia patients at home.

N-cadherin-based adhesion enhances Abeta release and decreases Abeta42/40 ratio.

In neurons, Presenilin 1(PS1)/gamma-secretase is located at the synapses, bound to N-cadherin. We have previously reported that N-cadherin-mediated cell-cell contact promotes cell-surface expression of PS1/gamma-secretase. We postulated that N-cadherin-mediated trafficking of PS1 might impact synaptic PS1-amyloid precursor protein interactions and Abeta generation. In the present report, we evaluate the effect of N-cadherin-based contacts on Abeta production. We demonstrate that stable expression of N-cadherin in Chinese hamster ovary cells, expressing the Swedish mutant of human amyloid precursor protein leads to enhanced secretion of Abeta in the medium. Moreover, N-cadherin expression decreased Abeta(42/40) ratio. The effect of N-cadherin expression on Abeta production was accompanied by the enhanced accessibility of PS1/gamma-secretase to amyloid precursor protein as well as a conformational change of PS1, as demonstrated by the fluorescence lifetime imaging technique. These results indicate that N-cadherin-mediated synaptic adhesion may modulate Abeta secretion as well as the Abeta(42/40) ratio via PS1/N-cadherin interactions.

[The effect of videophone communication (with skype and webcam)for elderly patients with dementia and their caregivers].

We conducted an intervention study to clarify how effectively videophone (Skype) was used in the communication for elderly patients with dementia cared at home and their caregivers. For a period of 12 weeks, a patient-caregiver pair(n = 6) communicated with a nurse via computer for 30 minutes once a week. The patient and the caregiver worked as a pair. Before and after the 12-week study period started, the intervention and control group (n = 7) patients were assessed with a cognitive scale (HDS-R), VAS, and a depression scale (SDS) for caregivers. The result on the 12th week showed signs of improvement on the intervention group in HDS-R and SDS. The intervention group kept no change in VAS, an expression of subjective feelings of happiness. Meanwhile, the control group significantly decreased in VAS. By the questionnaire for caregivers, many said that the videophone communication was a pleasure of the family and resulted in more family exchanges. Therefore, we consider that a videophone communication is useful for cognitive rehabilitation and the feelings of the patient, and it is also good for a satisfaction of the family.