[Vaccination therapy for Alzheimer's disease].
Explore the source record for details and available documents.
Alzheimer Disease↗
Biomedical subjects
Takeshi Tabira
Publications and source records attributed to Takeshi Tabira.
Development of a safe oral Abeta vaccine using recombinant adeno-associated virus vector for Alzheimer's disease.
A new oral vaccine for Alzheimer's disease was developed using recombinant adeno-associated virus vector carrying Abeta cDNA (AAV/Abeta). Oral administration of the vaccine without adjuvant induced the expression and secretion of Abeta1-43 or Abeta1-21 in the epithelial cell layer of the intestine in amyloid precursor protein transgenic mice. Serum antibody levels were elevated for more than six months, while T cell proliferative responses to Abeta was not detected. Brain Abeta burden was significantly decreased compared to the control without inflammatory changes. This oral AAV/Abeta vaccine seems to be promising for prevention and treatment of Alzheimer's disease.
Administration, Oral↗
[Alzheimer's disease due to presenilin mutations].
Explore the source record for details and available documents.
Age of Onset↗
[A molecular genetic overview of familial dementing disorders].
Explore the source record for details and available documents.
Alzheimer Disease↗
[Mild cognitive impairment (MCI)--overview].
Explore the source record for details and available documents.
Alzheimer Disease↗
[Treatment of Alzheimer disease: A beta vaccine].
Alzheimer disease (AD) is regarded as an amyloidosis of the brain, and, therefore, the prevention/deletion of beta amyloid deposition is one of the most promising target of the treatment. Particularly, immune-mediated strategy is now known as A beta vaccination, which is thought to be a highly feasible way being applicable to AD patients. The A beta vaccination was originated by Schenk et al. in 1999. Since active and passive immunization of amyloid precursor protein (APP) gene- transgenic mice showed significant reduction of beta amyloid deposits in the brain and the immunized mice showed improvement in cognitive functions, clinical trials were performed in US and Europe. However, the trial was suspended, because about 6% of patients who received the vaccine developed meningoencephalitis probably mediated by T cells reactive to A beta. Although the trial was halted, an autopsy case who had had the meningoencephalitis suggested the disappearance of senile plaques (Nicoll et al., 2003). Moreover, patients who developed antibodies that recognize senile plaques by immunohistochemistry showed significantly milder decline of cognitive functions than those who did not (Hock et al., 2003). Here, we report a safe and effective oral vaccine using adeno-associated virus vector carrying A beta cDNA tested in tg2576 mice.
Alzheimer Disease↗
A unifying model for functional difference and redundancy of presenilin-1 and -2 in cell apoptosis and differentiation.
Mutations in genes encoding the highly homologous proteins presenilin-1 and -2 (PS1 and PS2) are linked to the early onset of Alzheimer's disease (AD). Here, we report that polyclonal antibodies against Xenopus PSbeta (PS2), but not PSalpha (PS1), suppress the in vitro apoptotic activation of Xenopus egg extracts. To clarify the relationship between structural and functional differences in presenilins, we searched for presenilin homologues in various living sources, and found that presenilins were divided into three distinct groups, named alpha-, beta- and gamma-types, based on the size of the large hydrophilic loop (HL) regions as follows: HLalpha/HLbeta/HLgamma=4:3:6. No such size conservations were found in the N-terminal (NT) hydrophilic regions. Phylogenetic studies revealed that the presenilin genes were duplicated independently in different lineages of phyla/divisions, suggesting that there were functional requirements for and constraints on the generation and conservation of these HL sizes. On the basis of these findings, we propose a model postulating that both PS1 and PS2 can be differentiative or apoptotic when they are proteolytically processed within the HL regions or not, respectively, and PS1 may be more sensitive than PS2 to auto-proteolytic cleavage due to the larger size of the HL region of the former. Furthermore, the model assumes that C-terminal fragments (CTF) stabilized by phosphorylation may inhibit both the activities due to the dominant-negative effect. The model explains not only the functional redundancy but also apparently conflicting observations reported so far for PS1 and PS2.
Animals↗
Differential expression of presenilin-alpha and -beta (PSalpha and PSbeta) in Xenopus laevis: embryonic phosphorylation of PSalpha.
Mutations in genes encoding the highly homologous proteins, presenilin-1 and -2 (PS1 and PS2), are linked to the development of early-onset Alzheimer's disease. On the other hand, presenilins are known to play a critical role(s) in cell fate decisions during embryonic development in Caenorhabditis elegans. The messenger RNAs (mRNAs) of amphibian presenilin homologues PSalpha and PSbeta are most abundantly synthesized in the brain and the ovary, but are differentially degraded upon oocyte maturation and at the midblastula transition (MBT), respectively. In this study, we examined the spatiotemporal distribution of PSalpha and PSbeta proteins and their post-translational modification. The results were essentially consistent with the mRNA data and revealed moreover that PSalpha was present exclusively as processed molecules in the early embryos, while PSbeta was present mainly as unprocessed molecules (90%). Furthermore, the C-terminal fragment (CTF) of PSalpha was phosphorylated upon oocyte maturation and dephosphorylated at MBT, while no phosphorylation of the PSbeta CTF was detectable. Human PS1 CTF exogenously injected was also phosphorylated in Xenopus oocytes induced to mature in vitro by progesterone treatment. Two phosphorylation loci were mapped at Thr(320) and Ser(334) in the hydrophilic loop region of PSalpha. Our results suggest that PS1 and PS2 may play different roles under physiological conditions despite their high structural similarity.
Amino Acid Sequence↗
Genetic, clinical and pathological studies of CADASIL in Japan: a partial contribution of Notch3 mutations and implications of smooth muscle cell degeneration for the pathogenesis.
We have examined Notch3 mutations in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) whose samples were submitted to us in Japan. The subjects were composed of 21 Japanese, 1 Iranian, 1 Korean and 1 Canadian families. Mutations in the Notch3 gene were found in 7 of 24 families examined. These were R133C in two unrelated Japanese families, and R213K, C174F and R169C in each Japanese family. In addition, we have found R90C in an Iranian family and C174R in a Korean family. Thus, contribution of Notch3 gene mutations is less than one fourth of Japanese CADASIL families, suggesting the existence of other causative genes in CADASIL. It is also of interest to know that Notch3 mutant CADASIL exists in other Asian countries. We next examined the localization of Notch3 protein in the tissue by immunohistochemistry. It was restricted to the wall of arterioles in the brain and other organs. In the brain, there was no difference in the staining pattern among arterioles in the cortex, white matter and meninges. The staining was negative in the venule and capillaries as well as in neurons and glial cells. From the staining pattern, it was recognized to be expressed in the vascular smooth muscle cells in the adult tissue. In an autopsy case with R213K mutation, we could see numerous cerebral infarcts and arteriole wall degeneration with deposits of granular osmiophilic material (GOM). However, it is interesting to note that occlusion of arterioles was rarely observed and the GOM was negative for Notch3 staining. These findings suggest that hemodynamic abnormalities due to smooth muscle cell degeneration may be important in the pathogenesis of CADASIL.
Age of Onset↗
A clinical and pathological study of a Japanese case of Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex with family history.
This report concerns a Japanese family with neuropathological findings consistent with amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) in the Island of Guam. The proband was a 68-year-old woman with an 8-year history of parkinsonism which was followed by psychiatric symptoms and neurogenic amyotrophy 5 years after the onset. She had a family history of parkinsonism associated with dementia in all of her three siblings. They grew up in the Hobara village, a focus of amyotrophic lateral sclerosis in the Kii Peninsula of Japan in their childhood. Their parents were not consanguineous nor natives of the Kii Peninsula. The brain weight was 1040 g and there were mild frontal lobe atrophy, moderate atrophy of pes hippocampi, decoloration of the substantia nigra and locus coeruleus, and atrophy of the anterior root of the spinal cord. The microscopic examinations revealed degeneration of CA1 portion of the hippocampus to the parahippocampus gyrus, substantia nigra, locus coeruleus and spinal anterior horn with Bunina bodies. The spinal pyramidal tracts also mildly degenerated. Neurofibrillary tangles (NFT) were observed in the cerebral cortex, especially in the cortices from hippocampus to lateral occipitotemporal gyri, basal nucleus of Mynert, basal ganglia, thalamus, substantia nigra and widespread regions of the central nervous system through the brainstem to spinal cord including the nucleus of Onufrowitcz. In spite of a small amount of the senile plaques in the cerebral cortex and Lewy bodies in the substantia nigra and locus coeruleus, abundant NFT were distributed mainly in the third layer of the cerebral cortex, which is the characteristic feature of ALS/PDC. Thus, this was likely to be an ALS/PDC case outside the Guam Island. A tau mutation was not found on DNA analysis.
Aged↗
Saiko-ka-ryukotsu-borei-to, a herbal medicine, ameliorates chronic stress-induced depressive state in rotarod performance.
Exposure to chronic stress is thought to play an important role in the etiology of depression. This disorder has been shown to involve disruption of the hypothalamo-pituitary-adrenal (HPA) system and dysfunction of the prefrontal cortex (PFC). We have demonstrated that chronic stress in rats induces similar HPA disruption or a depressive state caused by a reduction of dopaminergic and serotonergic transmission in the PFC. We have also shown that saiko-ka-ryukotsu-borei-to, a herbal medicine, prevents such chronic stress-induced HPA disruption. However, the behavioral and neurochemical bases of this drug remain unclear. Here we examined the effects of saiko-ka-ryukotsu-borei-to on the depressive behavioral state and the reduction of transmission resulting from chronic stress. The chronic stress was induced by water immersion and restraint (2 h/day) for 4 weeks followed by recovery for 10 days. The treatment with saiko-ka-ryukotsu-borei-to (100, 300, or 1000 mg/kg p.o.) ameliorated the stress-induced depressive state in a dose-dependent manner, evaluated by a rotarod test. A microdialysis study indicated that the drug treatment significantly prevented the chronic stress-induced decreases in extracellular concentrations of dopamine and serotonin in the PFC. These results suggest that saiko-ka-ryukotsu-borei-to ameliorates the chronic stress-induced depressive state based on the prevention of PFC dysfunction. These findings provide important information for treatment of depression.
Animals↗
Familial amyotrophic lateral sclerosis and parkinsonism-dementia complex--tauopathy without mutations in the tau gene?
We present the clinical and genetic characteristics of a Japanese patient with neuropathologically confirmed familial amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC). The 68-year-old proband with an 8-year history of parkinsonism and neurogenic amyotrophy and her three siblings suffering from parkinsonism associated with dementia originated from the Kii Peninsula of Japan. The proband's brain exhibited mild frontal lobe atrophy, moderate atrophy of the pes hippocampi, decoloration of the substantia nigra and locus coerules, and atrophy of the anterior root of the spinal cord. Microscopic examinations revealed degeneration of the CA1 portion of the hippocampus to the parahippocampus gyrus, substantia nigra, locus coerules and the spinal anterior horn with Bunina bodies. Neurofibrillary tangles (NFTs) were observed in widespread regions of the central nervous system through the cerebral cortex to the spinal cord. The predominant distribution of NFTs in the the third layer of the cerebral cortex was compatible with the characteristic feature of ALS/PDC in Guam. No tau mutation was found in the proband. The lack of mutations in the tau gene not only in this patient but also in earlier reported cases of ALS in the Western Pacific seems to suggest that other genetic factors may be contributing to ALS/PDC.
Aged↗
[Familial non-Alzheimer dementia].
This is an abstract of my lecture on familial non-Alzheimer dementia. 1. Vascular dementia 1) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by autosomal dominant inheritance, smooth muscle cell degeneration and granular osmiophilic material (GOM) in arterioles, and Notch 3 mutations. 2) CARASIL This is an autosomal recessive vascular dementia with unknown etiology. 3) Familial amyloid angiopathy Familial cerebral hemorrhage and dementia is caused by mutations in amyloid precursor protein, cystatin c, and Bri genes. 2. Familial non-Alzheimer degenerative dementia 1) Dementia with Lewy bodies This is characterized by Alzheimer like dementia, visual hallucination and diffuse Lewy bodies which are formed by ubiquitinated alpha-synuclein. Occasionally, familial forms are reported, but gene mutations are unknown. 2) Frontotemporal dementia (FTD) FTDP-17 is characterized by tau mutations, character and personal changes, and disinhibition. The gene mutations were also found in familial forms of Pick's disease, corticobasal degeneration, and other tauopathies. 3) Familial British dementia (FBD), familial Danish dementia (FDD) FBD and FDD are characterized by Abri amyloid deposits, amyloid angiopathy and dementia. Mutations in Bri gene are reported. 4) Familial encephalopathy with neuroserpin inclusion bodies (FENIB) FENIB is characterized by dementia, Collins body and neuroserpin gene mutation.
Adaptor Proteins, Signal Transducing↗
Saiko-ka-ryukotsu-borei-to, an herbal medicine, prevents chronic stress-induced disruption of glucocorticoid negative feedback in rats.
Exposure to stress is known to precipitate or exacerbate many neuropsychiatric disorders such as depression. Abnormality of the neuroendocrine system, as shown by increased adrenal weight and attenuated glucocorticoid negative feedback, is frequently seen in depression. The aim of the present study is to clarify the usefulness of saiko-ka-ryukotsu-borei-to, an herbal medicine, in the treatment of abnormality of the neuroendocrine system using an experimental stress-depression model. Rats were subjected to water immersion and restraint for 2 h daily for 4 weeks (chronic stress), followed by recovery for 10 days. Saiko-ka-ryukotsu-borei-to was administered during the stress and recovery periods (100, 300, or 1000 mg/kg daily, p.o.) or only during the recovery period (1000 mg/kg). After the recovery period, the adrenal weight was measured, and glucocorticoid feedback ability was evaluated by a dexamethasone suppression test using 30 microg/kg dexamethasone. The administration of saiko-ka-ryukotsu-borei-to during the stress and recovery periods prevented the stress-induced increase in adrenal weight or the attenuated negative feedback in a dose-dependent manner. The administration of saiko-ka-ryukotsu-borei-to during the recovery period alone also ameliorated the abnormality of the neuroendocrine system. These results indicate that saiko-ka-ryukotsu-borei-to is effective against chronic stress-induced abnormality of the neuroendocrine system. Because some symptoms and symptomatic relapses in depressives are attributed to dysfunction of the hypothalamo-pituitary-adrenal axis, the present findings provide information important for prevention and treatment of depression.
Adrenal Glands↗
Alzheimer's disease with spastic paresis and cotton wool type plaques.
We reviewed Alzheimer's cases with spastic paresis and cotton wool type plaques in five Japanese and nine Caucasian cases. Most were early onset familial Alzheimer's disease with presenilin 1 mutations. The cotton wool type plaques were related to extremely high production of A beta 42, due mainly to presenilin 1 mutations and low immune responses. Cotton wool plaques were numerous in the entire central nervous system, including basal ganglia, brainstem and even in spinal cord. Cotton wool type plaques were composed of slightly electron dense synaptic structures, but amyloid fibrils were rarely found. Such a high accumulation of A beta 42 may cause degeneration of the pyramidal tract and basal ganglia from an early stage of Alzheimer's disease.
Adult↗
Characterization of an amyloid precursor protein-binding protein Fe65L2 and its novel isoforms lacking phosphotyrosine-interaction domains.
Human Fe65L2 is a member of the Fe65 protein family, which interacts with amyloid precursor protein (APP). Fe65L2 contains an N-terminal WW (Trp-Trp) domain followed by two phosphotyrosine-interaction domains, and consists of 486 amino acids. In the present study, we cloned and characterized two novel isoforms of Fe65L2, designated I-214 and I-245, which are produced by alternative splicing of the RNA. The splicing events disrupt the ability to bind with APP and low-density-lipoprotein-receptor-related protein. Fe65L2 was highly expressed in the brain, whereas I-214 and I-245 were expressed in various tissues. In HEK-293 cells, Fe65L2 was expressed in the nucleus and cytosol, whereas I-245 and I-214 were localized exclusively to the nucleus. The ratio of I-214 to Fe65L2 mRNA was increased by apoptotic stimuli. Although the overexpression of either Fe65L2 or I-214 did not significantly affect the half-life and maturation of APP, or the secretion of secreted APP, the secretion of beta-amyloid peptide (Abeta)40 and Abeta42 was increased by overexpression of Fe65L2, but not by that of I-214. These results suggest that Fe65L2 affects Abeta production and a possible regulation of Fe65L2 function by alternative splicing.
Alternative Splicing↗
Elevated levels of anti-CD9 antibodies in the cerebrospinal fluid of patients with subacute sclerosing panencephalitis.
Subacute sclerosing panencephalitis (SSPE) is a slowly progressive and highly lethal disease of the central nervous system. Although the primary cause of SSPE is believed to be persistent infection of neuron and glial cells by a measles virus, the precise mechanism of the progression of this disease has not yet been elucidated. CD9, a member of the tetraspanin family, is expressed in myelin and other nervous tissues. This study detected significant amounts of anti-CD9 antibodies in the cerebrospinal fluid (CSF) of all patients with SSPE included in the study. Anti-CD9 antibodies were also detected in the CSF of some patients with other neurologic disorders, but those patients had lower levels of anti-CD9 antibodies than did the patients with SSPE. The level of anti-CD9 antibodies was elevated and reached a peak that coincided with the appearance of brain atrophy. These findings shed light on a new aspect of the causes and progression of SSPE.
Adolescent↗