Attention to the domains of Revised Hasegawa Dementia Scale and Mini-Mental State Examination in patients with Alzheimer's disease dementia.

BACKGROUND: In Japan, Alzheimer's disease dementia (AD) is the most common cognitive disease, and the most widely used dementia screening tests are the Revised Hasegawa Dementia Scale (HDS-R) and Mini-Mental State Examination (MMSE). This study sought to elucidate the relationships of the individual domains of these tests with age and duration of school education in a large group of patients with AD. METHODS: Participants were 505 new outpatients diagnosed with AD who completed the HDS-R and MMSE at the first visit. We investigated the relationships of total and individual domains of these tests with age and duration of school education using the least squares method. Next, we plotted regression lines of the individual domain scores against the total test scores. RESULTS: Younger age and longer duration of school education were significantly associated with higher total HDS-R and MMSE scores in AD. Domain-specific results indicated that younger age was significantly associated with a higher immediate memory score on both the HDS-R and MMSE and with a higher orientation (time), repetition score on the MMSE. Longer duration of school education was significantly associated with a higher working memory score on the HDS-R and with higher serial 7, repetition and writing scores on the MMSE. In addition, shorter duration of school education was significantly associated with higher naming score on the MMSE. The regression lines of orientation of time, remote memory, visual memory, and verbal frequency hit the bottom on the HDS-R (4/30, 8/30, 4/30, and 6/30, respectively) and of orientation of time, serial 7, remote memory, and writing also hit the bottom on the MMSE (8/30, 9/30, 11/30, and 8/30, respectively). CONCLUSIONS: We should pay attention to age, duration of school education, and the individual domains when using the HDS-R or MMSE to assess patients with AD.

Families of patients with Alzheimer's disease dementia notice progression from symptoms of disorientation and visual memory disturbance.

BACKGROUND: Alzheimer's disease dementia (ADD) is the most common cognitive disease, but patients' families may notice some symptoms yet not recognise that they indicate ADD. This study investigated the symptoms that families notice as ADD as the disease progresses. METHODS: New outpatients diagnosed with ADD (n = 315) at five memory clinics completed two cognitive assessments, the Revised Hasegawa Dementia Scale (HDS-R) and Mini-Mental State Examination (MMSE). During an interview, family members completed the Functional Assessment Staging Test (FAST), an observational assessment tool that classifies ADD progression into seven stages. We then examined the relationship of the family-assessed FAST score with clinician-assessed HDS-R and MMSE domain scores by comparing between patients with FAST 1-3 and FAST 4-7. Next, we divided the FAST 4-7 group into the FAST 4-5 and FAST 6-7 subgroups and divided the FAST 1-3 group into the FAST 1-2 and FAST 3 subgroups. RESULTS: Surprisingly, half of the families did not recognise that the symptoms indicated ADD. Scores for orientation of time and place on the HDS-R and MMSE and for visual memory on the HDS-R were significantly related to family-assessed FAST score. Moreover, the orientation of time and place score on both scales and visual memory on the HDS-R were significantly worse in the FAST 4-7 group than in FAST 1-3 group. In the FAST 4-7 group, scores for age on the HDS-R and for reading and drawing on the MMSE were significantly worse in the FAST 6-7 subgroup. In the analysis of the FAST 1-3 group, there was no significant difference among the HDS-R and MMSE domains between the FAST 1-2 and FAST 3 subgroups. CONCLUSIONS: Family members of patients with ADD tend to notice the progression of ADD from the symptoms of disorientation and visual memory.

Neuropsychiatric Inventory Questionnaire Associated with Cognitive Function, Age, and Duration of Education in Patients with Alzheimer's Disease.

INTRODUCTION: Alzheimer's disease (AD) is the most common cognitive disease, and behavioral and psychological symptoms of dementia (BPSD) can place a heavy burden on families. The presence of these symptoms related to AD is commonly assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q). This study sought to clarify the relationship between scores on the 12-domain NPI-Q and individual factors in patients with AD. METHODS: Participants were 218 new outpatients with AD at five memory clinics. Cognitive function was assessed using the Revised Hasegawa Dementia Scale (HDS-R) and Mini-Mental State Examination (MMSE). We examined which individual factors were associated with the total NPI-Q score and the number of domains. We also examined which domains were associated with the factors identified. RESULTS: A higher total NPI score was significantly associated with lower scores on both cognitive assessments and a longer duration of education. Exhibiting symptoms on a greater number of domains was significantly associated with lower scores on both cognitive assessments, longer duration of education, and advanced age. The nighttime disturbances domain was significantly associated with lower scores on both cognitive assessments and advanced age. The delusions domain was significantly associated with lower education. CONCLUSIONS: BPSD may appear more easily with reduced quality of life and ongoing dissatisfaction. Effective individualized services are important for patients with AD, and therefore, we should account for age, cognitive function, and duration of education in the services provided.

Day service use and improved Serial 7 and Verbal fluency scores in patients with Alzheimer's disease.

BACKGROUND: Day services (DS) are provided as part of the Japanese public nursing care system. Recent studies have suggested a possible relationship between DS use and limited progression of Alzheimer's disease (AD). This study examined in detail the relationship between improvements in cognitive function and DS use in people with AD. METHODS: We retrospectively analysed Revised Hasegawa Dementia Scale (HDS-R) scores of 208 patients with AD at five memory clinics over a 6-month period. The patients were divided into a group that started using DS (n = 132) and a group that did not (n = 76) during the study period. We then compared each participant's total and item scores on the HDS-R between the first clinic visit and 6 months later also compared scores between DS users and non-users. RESULTS: DS non-users were younger, predominantly male, had longer school education, and better total HDS-R score at the first visit. After 6 months, DS users showed significantly improved total HDS-R score and individual Serial 7 and Verbal fluency scores. Immediate memory scores were comparable between the first visit and after 6 months. Among the DS users, more frequent participation in DS was significantly associated with improved total HDS-R score. CONCLUSIONS: DS use was significantly associated with improved HDS-R scores, especially for the Serial 7 and Verbal fluency tasks, and there was no deterioration in Immediate memory score. These results suggest the usefulness of DS participation as a non-pharmacological therapy.

Most families tend to realize progress of Alzheimer's disease when behavioural and psychological symptoms are obvious.

BACKGROUND: Alzheimer's disease (AD) is a common cognitive disease that can progress at an accelerating rate. Even with early diagnosis, the families might not recognize AD progressing unless behavioural and psychological symptoms of dementia (BPSD) develop. In many cases, discrepancies could exist between family-assessed AD stage and diagnosed AD stage. This study explored such discrepancies and potential clinical implications. METHODS: Participants were 161 new outpatients with AD or mild cognitive impairment at four memory clinics whose AD stage was diagnosed using the Revised Hasegawa Dementia Scale (HDS-R) and Mini-Mental State Examination (MMSE). We classified patients into four groups according to AD severity. Family members completed the Functional Assessment Staging (FAST) scale during an interview. We then assigned patients to three groups according to discrepancies between family-assessed and diagnosed AD stage. Families also completed the Neuropsychiatric Inventory Questionnaire (NPI-Q), which assesses 12 neuropsychiatric domains, in order to examine the presence of BPSD in relation to AD stage. RESULTS: Most families (74%-80%) assessed patients as having milder AD than the diagnosed stage. NPI-Q scores and duration of education significantly affected discrepancies with HDS-R and MMSE scores. The NPI-Q domains of anxiety, apathy/indifference, aberrant motor behaviours, and appetite/eating disturbance significantly affected family-assessed FAST. Families of patients with more years of education assessed the AD stage as more advanced than the diagnosed stage. Surprisingly, living together did not significantly affect the discrepancy. CONCLUSIONS: Most families assessed AD as milder than the clinically diagnosed AD stage. In addition, high NPI-Q scores and more years of school education significantly affected the discrepancy. Family-assessed FAST was significantly affected by the NPI-Q domains of anxiety, apathy/indifference, aberrant motor behaviours, and appetite/eating disturbance. These results suggest that obvious BPSD are significant factors for Japanese families to recognize AD progress.

Use of day services improved cognitive function in patients with Alzheimer's disease.

AIM: Day services (DS) are part of the public nursing care system in Japan. The purpose of DS is to help elderly individuals maintain mental and physical functions, eliminate feelings of isolation among homebound users, and reduce the burden of care on family members. However, the relationship between DS and the progression of Alzheimer's disease (AD) remains unclear. METHODS: We retrospectively analyzed 161 AD patients based on available Mini-Mental State Examination (MMSE) scores. The patients were divided into two groups: those who started to use DS (n = 106) and those who did not use DS (n = 55). We then compared the groups' MMSE scores between the first memory clinic visit and the 6-month point. RESULTS: There were no significant differences between the two groups with regard to sex and the number of family members, but the non-DS group was younger, had more education, and had better MMSE scores at the first visit. At 6 months, we found a significant improvement in the MMSE scores of DS users, reflecting improved cognitive function. In addition, lower MMSE score at the first visit was associated with greater improvement in MMSE score at 6 months. Interestingly, the frequency of DS use had no significant effect on MMSE score. However, after approximately 6 months, DS use significantly improved the cognitive function of AD patients. CONCLUSIONS: DS use significantly improved the cognitive function of AD patients. However, most DS users in Japan are older and have severe dementia. Patients who are younger, have more education, or have mild dementia dislike using DS. As a significant difference was found in the MMSE scores between the two groups after 6 months, DS use appears to be a useful non-drug therapy.

Japanese Old Stories Cognitive Scale: a screening test to detect cognitive disease and prompt visiting a memory clinic.

BACKGROUND: Early detection and diagnosis is critical in enhancing treatment outcomes for those with cognitive disease. However, most Japanese patients are averse to visiting mental health clinics or taking cognitive screening examinations. A new simple screening test is needed that is acceptable to patients and encourages them to visit a memory clinic if indicated. METHODS: We developed a brief screening examination, consisting of four common Japanese old stories, for detection of cognitive disease. A total of 311 patients at three outpatient memory clinics completed the screening test, responding to a 10-question, fill-in-the-blanks assessment. Questions were read aloud to patients with visual impairment, and we transcribed the spoken responses of patients who were physically incapable of writing. The Hasegawa Dementia Scale-Revised (HDS-R) and Mini-Mental State Examination (MMSE) were administered at the same time. RESULTS: Using the developed Japanese Old Stories Cognitive Scale (JOSS), we found significant differences between dementia and control or mild cognitive impairment (MCI) groups. The JOSS was less affected by education level than the HDS-R or MMSE, possibly because Japanese old stories are usually learned from family members during preschool years. The JOSS may be able to detect remote memory disturbance in addition to other cognitive dysfunctions. CONCLUSIONS: Most patients with AD, even in advanced stages, are averse to visiting a memory clinic because it can be difficult to accept any resulting diagnosis of cognitive disease. JOSS is a quick and simple screening tool to gather evidence of cognitive dysfunction and prompt a referral to a memory clinic. Patients with cognitive disease found the JOSS acceptable, and its high specificity could be useful in encouraging patients to visit already-crowded memory clinics for formal diagnosis and intervention.

Decreased levels of PDI and P5 in oligodendrocytes in Alzheimer's disease.

Protein disulfide isomerase (PDI) is a chaperone protein located in the endoplasmic reticulum (ER). Nitric oxide-induced S-nitrosylation of PDI inhibits its enzymatic activity, leading to protein accumulation and activation of the unfolded protein response. Protein disulfide isomerase P5 (P5) is a member of the PDI family that mostly localizes to the ER lumen. Both S-nitrosylated PDI and S-nitrosylated P5 are found in Alzheimer's disease (AD) brain. Previously, we showed that expression of the ER stress marker, growth arrest, and DNA damage protein (GADD34) was significantly increased in neurons and oligodendrocytes in AD brain. In the present study, we showed that PDI and P5 levels were significantly decreased in oligodendrocytes in the brains of AD patients and an AD mouse model. Interestingly, these decreases were evident before the animals displayed typical AD pathology. Because we previously showed that small short interfering RNA knockdown of PDI or P5 could affect the viability of neuronal cells under ER stress, dysfunction of PDI and P5 under ER stress could cause apoptosis of neuronal cells. In summary, we showed that the levels of PDI and P5 were significantly decreased in the oligodendrocytes of AD patients. This phenomenon was also found in an AD mouse model before the animals displayed AD pathology. The overall findings suggest that oligodendrocytes may play important roles in AD pathogenesis.

Relationship of the Japanese Old Stories Cognitive Scale With the Revised Hasegawa Cognitive Scale and Mini-Mental State Examination.

The Revised Hasegawa Dementia Scale (HDS-R) is the most widely used instrument to screen for dementia in Japan and is similar to the Mini-Mental State Examination (MMSE). The development of a quicker and simpler screening tool, the Japanese Old Stories Cognitive Scale (JOSS), was previously reported. A total of 953 new outpatients from 8 memory clinics in Japan completed the JOSS, HDS-R, and MMSE at first visit. We investigated the relationship of JOSS score with both the total and individual domain scores on the HDS-R and MMSE. We found a significant relation between JOSS score and total HDS-R and MMSE scores. In addition, JOSS score was significantly related to scores on 8 of the 9 HDS-R domains and 7 of the 11 MMSE domains. We obtained regression lines for JOSS score versus HDS-R and MMSE scores. JOSS score could be useful for predicting HDS-R and MMSE scores and thus in estimating cognitive functioning.

Living Arrangements and Education Duration Associated With Memory Clinic Attendance in Alzheimer's Disease.

Some new outpatients with mild cognitive impairment (MCI) or Alzheimer's disease (AD) do not regularly attend treatment appointments at memory clinics. To explore factors related to non-regular attendance, we divided new outpatients according to regular or non-regular attendance during the first 6 months of treatment and analyzed the relationship between individual patient factors and attendance. Approximately half of patients living alone did not regularly attend appointments. Living with family and longer duration of school education were significantly associated with regular attendance. Patients with mild or moderate AD attended appointments more regularly than patients with MCI or moderate-to-severe AD. Patients in Kyoto City had significantly better cognitive function than patients in satellite cities, and there were a significantly higher proportion of patients with MCI or AD at first visit in Kyoto City. Living arrangements and duration of education are important patient factors to consider to promote regular attendance at treatment appointments.

Protein disulfide isomerase-immunopositive inclusions in patients with amyotrophic lateral sclerosis.

The major pathological hallmarks of amyotrophic lateral sclerosis (ALS) are neuronal cytoplasmic inclusions (NCIs) and swollen neurites. Superoxide dismutase (SOD)-1-immunopositive NCIs are observed in patients with familial ALS (FALS), and TAR DNA-binding protein 43kDa (TDP-43)-immunopositive NCIs are found in patients with sporadic ALS (SALS). Protein disulfide isomerase (PDI) is a member of the thioredoxin superfamily and is believed to accelerate the folding of disulfide-bonded proteins by catalyzing the disulfide interchange reaction, which is the rate-limiting step during protein folding in the luminal space of the endoplasmic reticulum. Post mortem spinal cord specimens from five patients with SALS and one with FALS (I113T), and five normal controls were utilized in this immunohistochemical study. We found PDI-immunopositive swollen neurites and NCIs in the patients with ALS. Furthermore, PDI was colocalized with TDP-43 and SOD1 in NCIs. The accumulation of misfolding proteins may disturb axon transport and make swollen neurites. As the motor neuron is the longest cell in the nervous system, the motor system may selectively be disturbed. In conclusion, we assume that PDI is S-nitrosylated in the affected neurons, which inhibits its enzymatic activity and thus allows protein misfolding to occur in ALS.

Protein disulfide isomerase immunopositive glial cytoplasmic inclusions in patients with multiple system atrophy.

BACKGROUND: Glial cytoplasmic inclusions (GCIs) are the pathological hallmarks of multiple system atrophy (MSA) and α-synuclein is abnormally deposited in GCIs. Protein disulfide isomerase (PDI) is a member of the thioredoxin superfamily and is believed to accelerate the folding of disulfide-bonded proteins by catalyzing the disulfide interchange reaction, which is the rate-limiting step during protein folding in the luminal space of the endoplasmic reticulum (ER). Nitric-oxide-induced (NO-induced) S-nitrosylation of PDI inhibits its enzymatic activity, leading to the accumulation of polyubiquitinated proteins, and activates the unfolded protein response in neurodegenerative diseases. MATERIALS AND METHODS: Postmortem brain specimens from five patients with MSA and five normal control brains were utilized in this immunohistochemical study. RESULTS: We found GCIs positive for anti-PDI antibody in the brain of patients with MSA. In addition, we observed colocalization of α-synuclein and leucine-rich repeat kinase 2 (LRRK2) with PDI in GCIs. As LRRK2 immunoreactivity is associated with one of the earliest oligodendrocytic abnormalities in MSA, colocalization of LRRK2 and PDI in GCIs may be a link to the ER stress of glial cells in the early stages of MSA. CONCLUSIONS: In MSA, NO may inhibit PDI by inducing S-nitrosylation, which inhibits its enzymatic activity and thus allows protein misfolding to occur.

Medical interventions suppressed progression of advanced Alzheimer's disease more than mild Alzheimer's disease.

AIM: Alzheimer's disease (AD) is the most common neurodegenerative disease. In 2000, Mendiondo et al. reported on a model predicting that AD progresses at an accelerating rate and cognitive function worsens rapidly. Recently, anti-AD drugs and non-pharmacological intervention have been established, but the effect of intervention is unclear and might depend on the stage of AD progression. Here, we examined the prediction of Mendiondo's model in patients with different severities of AD. METHODS: A total of 163 new outpatients with AD at four memory clinics were retrospectively analyzed. The Revised Hasegawa Dementia Scale (HDS-R) and Mini-Mental State Examination (MMSE) were administered to all AD patients at the first visit and after approximately 12 months. We divided the patients into three groups according to scores at the first visit: mild, moderate and moderate-to-severe. We compared the scores at the first visit with those obtained after 12 months of anti-AD drug and non-pharmacological interventions. RESULTS: The HDS-R score improved from 14.5 to 15.0, and the MMSE score improved from 18.8 to 19.1 after 12 months of intervention. Also, the HDS-R and MMSE scores at the first visit were significantly associated with the annual change in the scores. Among the three groups, lower HDS-R and MMSE scores at the first visit were associated with significantly greater annual improvement in the scores after 12 months of intervention. CONCLUSIONS: Contrary to the prediction of Mendiondo's model, mild or moderate AD progressed more rapidly than moderate-to-severe AD under pharmacological and non-pharmacological interventions. Geriatr Gerontol Int 2020; 20: 324-328.

FKBP12-immunopositive inclusions in patients with α-synucleinopathies.

α-Synuclein (α-SYN), a presynaptic protein with the tendency to aggregate, is linked to α-synucleinopathies such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). α-SYN is the main component of round intracytoplasmic inclusions called Lewy bodies (LBs), which are the hallmark of PD and DLB. In addition, accumulation of amyloid-ß and neurofibrillary tangles as in the pathology of Alzheimer's disease has been found in the DLB brain. Glial cytoplasmic inclusions are an MSA-specific type of inclusion found in oligodendrocytes and mainly comprise α-SYN. FK506-binding protein (FKBP) 12 is a member of the immunophilin family with peptidyl-prolyl isomerase activity that promotes protein folding and is believed to act as a chaperone protein. Previous in vitro work indicated that FKBP12 accelerated α-SYN aggregation more than other peptidyl-prolyl isomerases. The enzymatic activity of FKBP12 increases the formation of α-SYN fibrils at subnanomolar concentrations. In this study, we found that FKBP12 colocalized with α-SYN in LBs and neurites in PD and DLB brains. Furthermore, FKBP12-immunopositive neurofibrillary tangles colocalized with phosphorylated tau in DLB and FKBP12-immunopositive glial cytoplasmic inclusions colocalized with α-SYN in MSA. These findings suggest that FKBP12 is linked to the accumulation of α-SYN and phosphorylated tau protein in α-synucleinopathies. FKBP12 may play important roles in the pathogenesis of α-synucleinopathies through its strong aggregation function. Thus, FKBP12 could be an important drug target for α-synucleinopathies.

Accumulation of Hsc70 and Hsp70 in glial cytoplasmic inclusions in patients with multiple system atrophy.

Heat shock proteins (HSPs) are molecular chaperones which can be induced by several kinds of stresses, and Hsc70 and Hsp70 are two major members of the family of 70 kDa HSPs. A major component of Lewy bodies (LBs) is alpha-synuclein, and Hsp70 has been observed in the LBs of brains with Parkinson's disease. Hsp70 has also been demonstrated to have the ability to suppress alpha-synuclein toxicity in vitro and in vivo. To investigate the precise role of Hsc70 and Hsp70 in patients with multiple system atrophy (MSA), which is another alpha-synuclein-related disease, we performed immunohistochemical studies on Hsc70 and Hsp70 using autopsied brains from 7 normal subjects and 15 patients with MSA. In the normal human brains, both neurons and glial cells, including oligodendrocytes, showed only weak Hsc70 and Hsp70 immunoreactivities. In contrast, in the brains with MSA, numerous glial cytoplasmic inclusions (GCIs) were intensely immunostained with Hsc70, and strong Hsc70 immunoreactivity was also found in glial intranuclear inclusions (GNIs), neuronal cytoplasmic inclusions (NCIs) and neuronal intranuclear inclusions (NNIs) as well as dystrophic neurites. The immunolabeling pattern for Hsp70 in the MSA brains was slightly different from that of Hsc70, and Hsp70 immunoreactivity was observed in many reactive astrocytes as well as some glial and neuronal inclusions. Our results suggest that the widespread accumulation of Hsc70 and Hsp70 may occur in brains with MSA, and that Hsc70 and Hsp70 may be associated with the pathogenesis of MSA.

Upregulated expression of 14-3-3 proteins in astrocytes from human cerebrovascular ischemic lesions.

BACKGROUND AND PURPOSE: Several types of chaperone proteins, such as heat shock proteins, have been reported to be associated with brain ischemia. The purpose of this study was to investigate whether an abnormal expression of 14-3-3 proteins, a novel type of molecular chaperones, occurs in human gray and white matter ischemic lesions. METHODS: We prepared formalin-fixed, paraffin-embedded sections from 33 autopsied brains, consisting of 7 normal controls, 4 cases with cerebral thrombosis, 5 cases with cerebral embolism, 8 cases with multiple lacunar infarctions, and 9 cases with Binswanger disease. Deparaffinized sections from all cases were immunostained with anti-14-3-3 antibodies using the avidin-biotin-peroxidase complex method, and some sections were also double-immunostained for 14-3-3 and glial markers. RESULTS: In the normal control brains, 14-3-3 immunoreactivity was mainly localized to the neuronal somata and processes. Strongly 14-3-3-immunopositive astrocytes were distributed in the infarct lesions and were particularly abundant in infarcts at the chronic stage. Intensely 14-3-3-immunolabeled astrocytes were also observed in the ischemic white matter lesions, and in the severely affected white matter lesions from patients with Binswanger disease, dense 14-3-3 immunoreactivity was found in clasmatodendritic astroglia as well as in reactive astrocytes. CONCLUSIONS: Our results suggest that 14-3-3 proteins may be induced mainly in astrocytes from human cerebrovascular ischemic lesions, and that the upregulated expression of 14-3-3 proteins in astrocytes may be involved in the formation of astrogliosis.

Increased GADD34 in oligodendrocytes in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-ß (Aß) and abnormally phosphorylated tau which contribute to endoplasmic reticulum (ER) stress. Previous studies demonstrated that Aß and a truncated fragment of Aß induced death of oligodendrocytes in vitro. In addition, a triple-transgenic AD mouse model exhibits significant region-specific alterations in myelination patterns at time points preceding the appearance of Aß accumulation. The growth arrest and DNA damage protein (GADD) 34 is up-regulated in response to ER stress and regulates subunit of protein phosphatase 1 (PP1) complex that dephosphorylates eukaryotic translation initiator factor 2α (elF2α). Thus, GADD34 is known as an ER stress regulator or ER stress marker. In a recent study, GADD34 was induced in the spinal cord glial cells of an amyotrophic lateral sclerosis (ALS) mouse model. It is interesting that reduced GADD34 delayed the onset of ALS and prolonged the survival period in the mouse model. In this study, we have demonstrated that GADD34 was increased in neurons of human AD brains. Additionally, this finding was also observed in oligodendrocytes in human AD brains. Furthermore, we showed that the expression levels of GADD34 in neurons and oligodendrocytes were significantly increased in the early stage of AD in the mouse model. As oligodendrocytes were more affected in the early stages of AD in this experimental model, ER stress of Aß oligomers may be more related to oligodendrocytes than to neurons. These results suggest that GADD34 could be a therapeutic target for preventing ER stress in neuronal cells in AD.

Protein disulfide isomerase P5-immunopositive inclusions in patients with Alzheimer's disease.

Amyloid plaques and neurofibrillary tangles (NFTs) are the major pathological characteristics of Alzheimer's disease (AD). NFTs are composed of tubular filaments and paired helical filaments containing polymerized hyperphosphorylated tau protein. Another feature of AD is excessive generation of nitric oxide (NO). Protein disulfide isomerase (PDI) is a chaperon protein located in the endoplasmic reticulum (ER). It was recently reported that NO-induced S-nitrosylation of PDI inhibits its enzymatic activity, leading to the accumulation of polyubiquitinated proteins, and activates the unfolded protein response. In addition, we previously reported the presence of PDI-immunopositive NFTs in AD. Here, we found that protein disulfide isomerase P5 (P5), which is a member of the PDI protein family, was co-localized with tau in NFTs. To our knowledge, this is the first report of P5-immunopositive inclusion in AD. Furthermore, we showed that S-nitrosylated P5 was present and the expression level of P5 was decreased in AD brains compared with that of control brains. We also demonstrated that the knock-down of PDI or P5 by siRNA could affect the viability of SH-SY5Y cells under ER stress. Previously, the observation of S-nitrosylated PDI in AD was reported. NO may inhibit P5 by inducing S-nitrosylation in the same manner as PDI, which inhibits its enzymatic activity allowing protein misfolding to occur in AD. The accumulation of misfolded proteins induces ER stress and may cause apoptosis of neuronal cells through S-nitrosylation and down-regulation of PDI and P5 in AD.

Derlin-1-immunopositive inclusions in patients with Alzheimer's disease.

Amyloid plaques and neurofibrillary tangles are the major pathological hallmarks of Alzheimer's disease. Neurofibrillary tangles are composed of filaments and paired helical filaments containing polymerized hyperphosphorylated tau protein. Derlin proteins are a family of proteins that are conserved in all eukaryotes, in which they function in endoplasmic reticulum-associated degradation. Protein disulfide isomerase (PDI) is a member of the thioredoxin superfamily and is believed to accelerate the folding of disulfide-bonded proteins in the luminal space of the endoplasmic reticulum. In this study, we found that derlin-1 and PDI were colocalized in neurofibrillary tangles in the brain of patients with Alzheimer's disease. Derlin-1 and PDI may work as partners to avoid the accumulation of unfolded proteins in Alzheimer's disease. Furthermore, we found that derlin-1 was immunopositive for neurofibrillary tangles and upregulated in Alzheimer's disease and that derlin-1 may play an important role in endoplasmic reticulum-associated degradation during the pathogenesis of Alzheimer's disease. We hypothesize that derlin-1 was upregulated to avoid the aggregation of unfolded proteins. Despite the upregulation of derlin-1, the functions of chaperone proteins and Alzheimer tau protein were lost and these proteins were also accumulated. Finally, they were involved in neurofibrillary tangles. These results suggest that derlin-1 may be associated with endoplasmic reticulum stress in neuronal cells in Alzheimer's disease.