A revision of JPOS/JASCC clinical guidelines for delirium in adult cancer patients: a summary of recommendation statements.

OBJECTIVE: The Japanese Psycho-Oncology Society and the Japanese Association of Supportive Care in Cancer have recently revised the clinical practice guidelines for delirium in adult cancer patients. This article reports the process of developing the revised guidelines and summarizes the recommendations made. METHODS: The guidelines were developed in accordance with the Medical Information Network Distribution Service creation procedures. The guideline development group, consisting of multi-disciplinary members, created three new clinical questions: non-pharmacological intervention and antipsychotics for the prevention of delirium and trazodone for the management of delirium. In addition, systematic reviews of nine existing clinical questions have been updated. Two independent reviewers reviewed the proposed articles. The certainty of evidence and the strength of the recommendations were graded using the grading system developed by the Medical Information Network Distribution Service, following the concept of The Grading of Recommendations Assessment, Development, and Evaluation system. The modified Delphi method was used to validate the recommended statements. RESULTS: This article provides a compendium of the recommendations along with their rationales, as well as a short summary. CONCLUSIONS: These revised guidelines will be useful for the prevention, assessment and management of delirium in adult cancer patients in Japan.

[Management of Delirium in Patients with Cancer].

Delirium is a condition in which the main symptom is a mild disturbance of consciousness caused by a physical abnormality or medication, and various symptoms such as cognitive dysfunction, hallucinations, delusions, and mood swings appear with any disease. Delirium is frequently observed in patients with cancer, especially in the terminal stage, and is observed in about 90% of patients just before death. Hypercalcemia due to bone metastases, brain metastases, and the use of opioids and steroids for symptom relief are direct factors in the development of delirium. Furthermore, there are many opportunities to encounter delirium at the end of life caused by conditions that are difficult to recover from, such as brain metastasis, liver failure, and hypoxic encephalopathy. In the management of delirium, "search for the cause(s)and its treatment"and"environmental adjustment"are the most important. Then, pharmacotherapy is considered to reduce the severity of delirium. Antipsychotics are the basic medication of choice. The route of administration, half-life, dosage form, adverse events of medication, as well as patient factors such as the presence or absence of diabetes and the subtype of delirium should be comprehensively considered when selecting a medication. The timing of medication discontinuation should also be kept in mind once medication therapy is initiated. On the other hand, when delirium is caused by factors that are difficult to recover from, the goal of treatment is to alleviate the painful symptoms caused by delirium, and it is important to take a holistic approach for patients and family members.

Rasch Analysis of the Assessment of Quality of Activities (A-QOA), an Observational Tool for Clients With Dementia.

IMPORTANCE: The Assessment of Quality of Activities (A-QOA) is an observation-based tool for assessing the strength of engagement in an activity by the person performing it in a natural context. By quantifying the quality of engagement, the A-QOA can help occupational therapy practitioners be better able to select meaningful activities and more clearly understand the effectiveness of various choices. OBJECTIVE: To examine use of the A-QOA as a valid unidimensional scale and to clarify preliminary results on its internal scale validity and item reliability using the Rasch model. PARTICIPANTS: One hundred thirty-one participants with dementia performing 262 activities. OUTCOMES AND MEASURES: We used the Rasch model to clarify the psychometric properties of A-QOA's measurement quality. RESULTS: Rasch analysis revealed that 21 of the 25 items reached an acceptable level of fit, and 4 did not. After eliminating the 4 misfitting items, the resulting A-QOA was determined to have both acceptable internal scale validity and item separation reliability, which are fundamental psychometric properties of a clinical observational instrument. CONCLUSIONS AND RELEVANCE: The A-QOA can be used to quantitatively assess the strength of engagement in an activity by the person performing it by using the observational method. WHAT THIS ARTICLE ADDS: In clinical settings, the A-QOA can be used both to select activities for clients with dementia and to quantitatively show the effects of occupational therapy interventions.

JPOS/JASCC clinical guidelines for delirium in adult cancer patients: a summary of recommendation statements.

BACKGROUND: The Japanese Psycho-Oncology Society and Japanese Association of Supportive Care in Cancer recently launched the clinical practice guidelines for delirium in adult cancer patients. The aim of the guidelines was to provide evidence-based recommendations for the clinical assessment and management of delirium in cancer patients. This article reports the process of developing the guideline and summarizes the recommendations made. METHODS: The guidelines were developed in accordance with the Medical Information Network Distribution Service creation procedures. The guideline development group, consisting of multidisciplinary members, formulated nine clinical questions. A systematic literature search was conducted to identify relevant articles published prior to through 31 May 2016. Each article was reviewed by two independent reviewers. The level of evidence and the strength of the recommendations were graded using the grading system developed by the Medical Information Network Distribution Service, following the concept of The Grading of Recommendations Assessment, Development and Evaluation system. The modified Delphi method was used to validate the recommendation statements. RESULTS: This article provides a summary of the recommendations with rationales for each, as well as a short summary. CONCLUSIONS: These guidelines will support the clinical assessment and management of delirium in cancer patients. However, additional clinical studies are warranted to further improve the management of delirium.

The use of psychosocial support services among Japanese breast cancer survivors.

BACKGROUND: This study aimed to investigate the use of psychosocial support services, the intention to use these services, and to elucidate the characteristics of survivors most likely to use support services among Japanese breast cancer survivors. METHODS: We invited breast cancer survivors to complete an online questionnaire via an email sent to subscribers of a non-profit organization mailing list. We asked participants questions related to demographics, opinions on the state of psychosocial support services, and their interest in using these services. Participants were also asked to complete the Hospital Anxiety and Depression Scale and the Brief Cancer Worry Inventory (BCWI). RESULTS: We analyzed the data of 171 participants. Those who used some form of psychosocial support service constituted 50.9% of the participant population. Participants used cancer consulting and support center services (13.5%), hospital and non-hospital support groups (12.9%, respectively), psychiatry (11.1%), hospital and non-hospital cancer salons (8.8%, respectively), psychosomatic medicine (8.2%), therapist counseling (6.4%) and psycho-oncology department services (4.1%). Non-users who suffered from adjustment disorders or major depression (52.1%) reported higher total BCWI and the subscale scores had no concrete plans to use psychosocial support services. CONCLUSIONS: The usage levels of psychiatry, psychosomatic medicine and psycho-oncology services in our study were higher than those reported in any previous Japanese study within the psycho-oncology field. Participants joining a breast cancer survivors' mailing list, or their being female, may have led to a higher use of such services. A high degree of distress does not necessarily lead cancer survivors to seek psychosocial support services.

Association between depressive symptoms and changes in sleep condition in the grieving process.

PURPOSE: Bereaved families often suffer from insomnia and depression. However, the associations between depressive state and changes in sleep condition during the grieving process have not been investigated. This study aimed to clarify the prevalence of insomnia symptoms and to explore associations between present depressive state and changes in sleep condition in the grieving process in bereaved families of Japanese patients with cancer. METHODS: A cross-sectional, multicenter survey was conducted in 103 certified palliative care units. A questionnaire asking insomnia symptoms and depressive symptoms by the Center for Epidemiological Studies Depression Scale (CES-D) was mailed to bereaved families (N = 987). The association between present depressive state (CES-D ≥7) and sleep conditions in the grieving process were analyzed. RESULTS: A total of 561 families were enrolled for analysis. Fifty-three percent of family members were considered to be in a depressive state at the time of the investigation. Prevalence of past insomnia was 86.5% at "within a few weeks before the patient's death" (T1) and 84.5% at "within 6 months after the patient's death" (T2) in all bereaved family members. However, in contrast to decreased severity of insomnia between T1 and T2 in the non-depressive group (p < 0.05), severity of insomnia was unchanged in the depressive group during this period (p = 0.139). CONCLUSIONS: Insomnia symptoms are highly prevalent and may be associated with posthumous depressive state in bereaved Japanese families. These results suggest the need for careful observation of changes in sleep condition during the grieving process.

[Cancer-related Cognitive Impairment: Current Knowledge and Future Challenges].

Cancer patients often suffer from various distresses, including cognitive impairment. Cognitive impairment during and after cancer diagnosis and treatment are collectively called "Cancer-related cognitive impairment (CRCI)". The number of publications about cognitive impairment due to cancer therapy, especially chemotherapy, hormonal therapy, and radiotherapy, has been growing. Patients often worry not only about their disease condition and therapies, but also experience concerns regarding their memory, attention, and ability to concentrate. Even subtle CRCI can have a significant impact on social relationships, the ability to work, undergo treatment, accomplish meaningful goals, and the quality of life. Longitudinal studies of cancer patients indicated that up to 75% experience CRCI during treatment. Furthermore, CRCI may persist for many years following treatment. However, it is not well understood by most physicians and medical staff. CRCI can be mediated through increased inflammatory cytokines and hormonal changes. In addition, the biology of the cancer, stress, and attentional fatigue can also contribute to CRCI. Genetic factors and co-occurring symptoms may explain some of the inter-individual variability in CRCI. Researchers and patients are actively trying to identify effective interventional methods and useful coping strategies. Many patients are willing to discuss their disease condition and future treatment with medical staff and/or their families. Some patients also hope to discuss their end-of-life care. However, it is difficult to express their will after developing cognitive impairment. Advance care planning (ACP) can help in such situations. This process involves discussion between a patient, their family, and clinicians to clarify and reflect on values, treatment preferences, and goals to develop a shared understanding of how end-of-life care should proceed. The number of cancer patients with cognitive impairment has been increasing owing to the super-aging of society. Psychiatrists need to develop appropriate care for them and understand the value of ACP. In this review, an outline of CRCI is given, especially related to cancer therapy such as chemotherapy, hormonal therapy, and radiation therapy. In addition, the importance of ACP to facilitate a living will for patients likely to develop impaired cognitive functions in the future is described.

Usefulness of Gabapentin as an Alternative/Adjunct Therapy for Delirium: A Retrospective Observational Study.

BACKGROUND: Antipsychotics are commonly used to treat delirium but can adversely affect the extrapyramidal and cardiac conduction systems. Antipsychotic use has also been reported to be associated with increased mortality in older adults. Therefore, alternative and adjunct medications for delirium are necessary. We retrospectively assessed the efficacy and safety of gabapentin (GBP) as an alternative and adjunct medication for delirium. METHODS: We retrospectively investigated the records of patients with delirium treated with GBP (71 patients; median age, 81 years; interquartile range, 76-87.5 years; 54.9% males) at a general hospital. We examined duration to delirium improvement, as assessed by the Intensive Care Delirium Screening Checklist (ICDSC) and DSM-5 criteria, as well as adverse events. RESULTS: The median (interquartile range) GBP dose was 200 mg (150-350 mg) /day. A total of 71.8% and 85.9% of the patients failed to meet the diagnostic criteria for delirium at 2 days and 5 days after initial administration, respectively (p<0.05). In subgroup analysis, patients with a history of epilepsy or cerebrovascular disease responded better to GBP than did those without such histories, suggesting that patients with abnormal/borderline neuronal activity respond to GBP even though they do not exhibit seizures. GBP did not induce extrapyramidal symptoms, cardiac conduction disturbances, hyperglycemia, or epilepsy but caused sleepiness and myoclonus. CONCLUSIONS: GBP may improve delirium with fewer adverse effects and may be a safe alternative or adjunct treatment for delirium. Dosage adjustment may be necessary to prevent sleepiness.

Culturally Adapted RN-MD Collaborative SICP-Based ACP: Feasibility RCT in Advanced Cancer Patients.

CONTEXT: Cultural adaptation is essential for optimizing programs centered around autonomy, such as the Serious Illness Care Program (SICP), especially for populations valuing family-involved decision-making. OBJECTIVES: We aimed to evaluate the feasibility and efficacy of a culturally adapted SICP-based nurse-physician collaborative Advance Care Planning (ACP) intervention tailored for patients with advanced cancer who prefer family-involved decision-making. METHODS: Oncology nurses, extensively trained and closely collaborating with physicians, conducted structured discussions with patients in the intervention group. The culturally adapted SICP-based ACP intervention was supplemented with trust-building, family involvement, and understanding of patient values. Primary inclusion criteria included patients within six weeks of initiating first-line palliative chemotherapy. Primary endpoints were achieving a 70% completion rate and assessing spiritual well-being (FACIT-Sp) at six months. Secondary endpoints included anxiety (GAD-7), depression (PHQ-9), quality of life (QOL) (CoQoLo), and ACP progress (ACP Engagement Scale) at the same interval. RESULTS: Forty-one patients (67.2%) completed the six-month follow-up, falling short of the targeted completion rate. The least-squares mean change from baseline in spiritual well-being at six months was 3.00 in the intervention group and -2.22 in the standard care group (difference, 5.22 points; 95% confidence interval, 1.38-9.06; P = 0.009). Similar superiority of the intervention was observed in QOL and ACP progress. CONCLUSION: Despite not meeting the targeted completion rate, the intervention group demonstrated enhanced spiritual well-being, QOL, and ACP progress. Our findings suggest revisions to the intervention manual to improve feasibility and to progress to an efficacy-focused randomized controlled trial.

Paclitaxel induces neurotoxicity through endoplasmic reticulum stress.

Due to chemotherapy, the majority of breast cancer patients survive, but frequently complain of chemotherapy-associated cognitive impairment. This phenomenon is termed "chemobrain" or "chemofog" in the literature. However, its mechanisms are unclear. The objective of this study was to investigate the mechanisms of paclitaxel (Px)-induced neurotoxicity, with a focus on endoplasmic reticulum (ER) stress. To investigate Px-induced neurotoxicity and ER stress induction, SK-N-SH cells were treated with 1, 10, 50, and 100 µM Px for 24 h. Neurotoxicity was assessed using MTS viability assays, and ER stress was assessed by evaluating the expression of phosphorylated elF2α (phospho-eIF2α), C/EBP homologous protein (CHOP), and cleaved caspase 4 and caspase 3 (the active form of each caspase). Furthermore, to investigate whether immunoglobulin heavy-chain binding protein (BiP) inducer X (BIX), which induces the molecular chaperone BiP, could attenuate Px-induced neurotoxicity, SK-N-SH cells were pre-treated for 12 h with 3.5 µM BIX before Px treatment. Neurotoxicity was observed in SK-N-SH cells treated with Px in a dose-dependent manner compared with vehicle control. Furthermore, phospho-eIF2α, CHOP, and activated caspase 4 and caspase 3 were significantly induced in Px-treated cells. In addition, pre-treatment with BIX significantly attenuated the induction of CHOP and activated caspase 4 and caspase 3. The viability of BIX pre-treated cells prior to Px treatment was significantly increased compared with cells that were not treated with BIX. Our results suggest that Px induces neurotoxicity in part through activating the ER stress response. Our findings should contribute to novel approaches regarding the mechanism of Px-induced neurotoxicity, including chemobrain.

Involvement of endoplasmic reticulum stress in tauopathy.

Tauopathy is a pathological condition with an abnormal intracellular accumulation of tau protein in neurons and glias, which is a feature of Alzheimer's disease (AD) as well as frontotemporal lobar degenerations (FTLD). Recent reports showed that tauopathy occupies an important position for pathological process of dementia generally. Previously, we reported that endoplasmic reticulum (ER) stress has an influence on the onset of AD. In addition, some reports on brain autopsy findings suggest that ER stress is associated with AD and tauopathy. However, the mechanism underlying the association between ER stress and tauopathy is still unknown. Here, we show that ER stress, induced by glucose deprivation or chemicals, increases total endogenous tau protein in cultured neurons and primary cultured neurons. Under ER stress, no significant differences were observed in the transcription of tau, and no differences were observed in the translation of tau with or without the 5'-untranslated region (5'UTR) of tau. In contrast, the degradation rate of tau was decreased by 20% under ER stress. ER stress reduced the binding between tau and carboxyl terminus of Hsc70-interacting protein (CHIP), ubiquitin E3 ligase for tau. These results suggest that ER stress increases total tau protein and its mechanism is due to the decrease in the binding between tau and CHIP, which delays the degradation of tau protein through the ubiquitin-proteasome pathway. This mechanism may provide clue to treatment for tauopathy.

Preliminary study of assessing cognitive impairment in older patients with chronic obstructive pulmonary disease by using a cognitive functional assessment tool via a touchscreen personal computer.

Background: Unique cognitive impairments related to chronic obstructive pulmonary diseases (COPD) have been increasingly reported. Considering the dementia risk and medication management, older patients with COPD should be evaluated for cognitive impairment. This study aimed to examine whether specific cognitive impairments related to COPD could be detected by an assessment tool using a touchscreen personal computer (PC) in older patients with COPD. Methods: This study included 28 older male patients with COPD and 30 healthy older male individuals. A touchscreen PC-based cognitive assessment application called CogEvo was used to assess and compare the cognitive function according to five domains: spatial cognition, orientation, working memory, executive function, and attention. Results: Analysis of variance showed an interaction effect on the indices of cognitive function based on five domains between the two groups, indicating differences in the characteristics of cognitive function in such groups. Betweengroup comparisons as a subtest showed that attention, executive function, and working memory were significantly lower in the COPD group than in the healthy group. Conclusions: CogEvo can detect specific cognitive impairments associated with COPD, suggesting that it can be potentially used as a screening tool for cognitive impairment in older patients with COPD.

Comparison of Psychological Quality of Life Between Long-Term Survivors of Childhood Cancer and Their Families.

Purpose: Although treatment outcomes for childhood cancer have improved in recent years, some patients continue to experience physical symptoms and psychological stress several years after the end of treatment. This study aimed to examine the correlation between the quality-of-life (QOL) scores of childhood cancer survivors (CCSs) aged 18-39 and (1) their families and (2) the time since the end of treatment. Methods: Measuring the QOL of CCSs attending the long-term follow-up (LTFU) and those of their families. The Short-Form Health Survey (SF-36) was used for CCSs and the Caregiver Quality of Life Index-Cancer (CQOLC) for their families. Spearman's rank correlation analyses were used to examine the relationship between the CCSs' and their families' QOL and the time since the end of treatment. Results: Twenty-nine CCSs (mean age, 24.2 years; mean the time since the end of treatment, 13.9 years), each paired with one family member, were included. Time since the end of treatment was positively correlated with the CCSs' QOL on the physical component score (ρ = 0.42, p = 0.03) and negatively correlated with mental health (MH) (ρ = -0.50, p = 0.01), a subscale of the mental component score (MCS). Furthermore, the CCSs' QOL on the MCS was positively correlated with their families' QOL scores (ρ = 0.58, p < 0.01). Conclusion: Psychological stress may persist in CCSs long after treatment, even when physical symptoms improve. Therefore, it is necessary to establish a comprehensive support system for the LTFU of CCSs, including MH care and QOL monitoring for patients and their families.

Sigma-1Rs are upregulated via PERK/eIF2α/ATF4 pathway and execute protective function in ER stress.

Sigma-1 receptors (Sig-1Rs) are the ER resident proteins. Sig-1Rs in the brain have been reported to be significantly reduced in patients with schizophrenia. The impediment of regulating Sig-1Rs expression levels increases the risk for schizophrenia. Thus elucidating the mechanism regulating Sig-1Rs expression might provide the strategy to prevent mental disorders. In this study, we have demonstrated that Sig-1Rs were transcriptionally upregulated by ATF4 in ER stress. Moreover, ATF4 directly bounds to the 5' flanking region of Sig-1R gene. The reporter activities using this region were enhanced in ER stress, or by ATF4 alone. The reporter activities with the pathogenic polymorphisms (GC-241-240TT, T-485A) were reduced. In addition, the processing of Caspase-4 was inhibited by Sig-1Rs. These results indicate that Sig-1Rs are transcriptionally upregulated via the PERK/eIF2α/ATF4 pathway and ameliolate cell death signaling. This study is the first report identifying the transcription factor regulating Sig-1Rs expression.

Low-Dose Trazodone for Delirium in Patients with Cancer Who Received Specialist Palliative Care: A Multicenter Prospective Study.

Background: Clinical usefulness of trazodone for delirium in patients receiving palliative care is unclear. Objectives: To examine the safety and effectiveness of trazodone for delirium. Design: A secondary analysis of a multicenter prospective observational study. Setting/Subjects: The setting involves nine psycho-oncology consultation services and 14 inpatient palliative care units in Japan. Measurements: The measurement involves the Delirium Rating Scale (DRS) Revised-98 for effectiveness and the CTCAE (Common Terminology Criteria for Adverse Events) version 4 for safety assessments. Results: Thirty-eight patients enrolled the study. Mean age was 75 years. After three-day observation, the DRS total score (11.6 ± 5.3 to 8.7 ± 6.5 [difference -2.9, 95% confidence interval -5.3 to -0.5, p = 0.02]); sleep-wake cycle disturbance (p = 0.047), lability of affect (p < 0.001), and motor agitation subscales (p < 0.001) were significantly decreased. The most frequent adverse event was somnolence (n = 9). Conclusions: Low-dose trazodone treatment was generally safe and may be effective in reducing delirium severity.

Perception Gap in Health-Related Quality of Life Between Young Adult Survivors of Childhood Cancer and Their Family.

Young adult survivors of childhood cancer may have a perception gap with their families. Patients aged 18-39 years after treatment of cancer and their families (28 pairs) completed a survey that contained questions on health-related quality of life using the 36-item short form survey. There was a significant difference in the role-social component score (mean difference -2.23; p = 0.04) with family reporting higher scores than patients. Families may overestimate the social function of cancer survivors, emphasizing the importance of the long-term follow-up by taking into account the risk of a gap (IRB approval No.: R2257-1).

KIBRA genetic polymorphism influences episodic memory in Alzheimer's disease, but does not show association with disease in a Japanese cohort.

BACKGROUND/AIMS: A single-nucleotide polymorphism (SNP) in the KIBRA gene, rs17070145, was reported to be significantly associated with episodic memory in cognitively normal cohorts. This observation has expanded genetic studies on KIBRA to Alzheimer's disease (AD). Importantly, the association between KIBRA and episodic memory in AD has never been addressed. In this study, we investigated whether the KIBRA rs17070145 SNP influences AD episodic memory and the disease in a Japanese cohort. METHODS: Blood samples from 346 AD patients and 375 normal cognitive controls were collected and genotyped for rs17070145. Episodic memory was measured in 32 AD patients, diagnosed for the first time, by use of the Rivermead Behavioral Memory Test (RBMT). RESULTS: We found that KIBRA C allele carriers scored significantly lower than KIBRA non-C carriers on both RBMT total profile score (p = 0.042, effect size = 0.84) and RBMT total screening score (p < 0.001, effect size = 1.42). The KIBRA gene did not show association with AD in our Japanese cohort. CONCLUSION: Our results evidence a strong association between the KIBRA gene and episodic memory impairment in AD, but show no influence on AD in our Japanese cohort. We propose that KIBRA might have an effect similar to cognitive reserve.

Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer's disease.

It has been established for a long time that brain glucose metabolism is impaired in Alzheimer's disease. Recent studies have demonstrated that impaired brain glucose metabolism precedes the appearance of clinical symptoms, implying its active role in the development of Alzheimer's disease. However, the molecular mechanism by which this impairment contributes to the disease is not known. In this study, we demonstrated that protein O-GlcNAcylation, a common post-translational modification of nucleocytoplasmic proteins with beta-N-acetyl-glucosamine and a process regulated by glucose metabolism, was markedly decreased in Alzheimer's disease cerebrum. More importantly, the decrease in O-GlcNAc correlated negatively with phosphorylation at most phosphorylation sites of tau protein, which is known to play a crucial role in the neurofibrillary degeneration of Alzheimer's disease. We also found that hyperphosphorylated tau contained 4-fold less O-GlcNAc than non-hyperphosphorylated tau, demonstrating for the first time an inverse relationship between O-GlcNAcylation and phosphorylation of tau in the human brain. Downregulation of O-GlcNAcylation by knockdown of O-GlcNAc transferase with small hairpin RNA led to increased phosphorylation of tau in HEK-293 cells. Inhibition of the hexosamine biosynthesis pathway in rat brain resulted in decreased O-GlcNAcylation and increased phosphorylation of tau, which resembled changes of O-GlcNAcylation and phosphorylation of tau in rodent brains with decreased glucose metabolism induced by fasting, but not those in rat brains when protein phosphatase 2A was inhibited. Comparison of tau phosphorylation patterns under various conditions suggests that abnormal tau hyperphosphorylation in Alzheimer's disease brain may result from downregulation of both O-GlcNAcylation and protein phosphatase 2A. These findings suggest that impaired brain glucose metabolism leads to abnormal hyperphosphorylation of tau and neurofibrillary degeneration via downregulation of tau O-GlcNAcylation in Alzheimer's disease. Thus, restoration of brain tau O-GlcNAcylation and protein phosphatase 2A activity may offer promising therapeutic targets for treating Alzheimer's disease.

The production ratios of AICDε51 and Aß42 by intramembrane proteolysis of ßAPP do not always change in parallel.

BACKGROUND: During intramembrane proteolysis of ß-amyloid protein precursor (ßAPP) by presenilin (PS)/γ-secretase, ε-cleavages at the membrane-cytoplasmic border precede γ-cleavages at the middle of the transmembrane domain. Generation ratios of Aß42, a critical molecule for Alzheimer's disease (AD) pathogenesis, and the major Aß40 species might be associated with ε48 and ε49 cleavages, respectively. Medicines to downregulate Aß42 production have been investigated by many pharmaceutical companies. Therefore, the ε-cleavages, rather than the γ-cleavage, might be more effective upstream targets for decreasing the relative generation of Aß42. Thus, one might evaluate compounds by analyzing the generation ratio of the ßAPP intracellular domain (AICD) species (ε-cleavage-derived), instead of that of Aß42. METHODS: Cell-free γ-secretase assays were carried out to observe de novo AICD production. Immunoprecipitation/MALDI-TOF MS analysis was carried out to detect the N-termini of AICD species. Aß and AICD species were measured by ELISA and immunoblotting techniques. RESULTS: Effects on the ε-cleavage by AD-associated pathological mutations around the ε-cleavage sites (i.e., ßAPP V642I, L648P and K649N) were analyzed. The V642I and L648P mutations caused an increase in the relative ratio of ε48 cleavage, as expected from previous reports. Cells expressing the K649N mutant, however, underwent a major ε-cleavage at the ε51 site. These results suggest that ε51, as well as ε48 cleavage, is associated with Aß42 production. Only AICDε51, though, and not Aß42 production, dramatically changed with modifications to the cell-free assay conditions. Interestingly, the increase in the relative ratio of the ε51 cleavage by the K649N mutation was not cancelled by these changes. CONCLUSION: Our current data show that the generation ratio of AICDε51 and Aß42 do not always change in parallel. Thus, to identify compounds that decrease the relative ratio of Aß42 generation, measurement of the relative level of Aß42-related AICD species (i.e., AICDε48 and AICDε51) might not be useful. Further studies to reveal how the ε-cleavage precision is decided are necessary before it will be possible to develop drugs targeting ε-cleavage as a means for decreasing Aß42 production.