Search

TMEM119 and purinergic receptor P2Y12 (P2RY12), which are not expressed by recruited peripheral blood macrophages, are proposed to discriminate microglia from macrophages. Therefore, we investigated the distribution patterns of microglia and macrophages in 10 concentric lesions from four autopsied Baló's disease cases and one neuromyelitis optica spectrum disorder (NMOSD) case, using quantitative immunohistochemistry for the markers TMEM119, P2RY12, CD68, CD163 and GLUT5. Three cases with Baló's disease had distal oligodendrogliopathy (DO) showing preferential loss of myelin-associated glycoprotein and early active demyelination in the outermost demyelinating layer (termed DMY-MO). In DMY-MO with DO, TMEM119-positive activated microglia expressing upregulated GLUT5 but markedly downregulated P2RY12 were significantly increased. These activated microglia expressed inducible nitric oxide synthase. Oligodendrocytes and their precursors showed apoptotic-like nuclear condensation in DMY-MO. TMEM119-negative and CD68/CD163-positive macrophages were distributed throughout the lesion center of DMY-MO with DO and these cells demonstrated foamy morphology only in the inner portion but not in the outer portion. In concentric demyelinating lesions from another Baló's case and lamellar demyelinating lesions in an NMOSD case, which had late active demyelination without DO, the densities of TMEM119-, GLUT5- and P2RY12-positive microglia with ramified morphology were significantly increased in myelinated layers but not in demyelinating layers. In particular, in the NMOSD case, TMEM119-positive microglia were confined to the outer portion of the myelinated layers. CD68-positive macrophages with foamy morphology also expressing CD163 accumulated in myelinated as well as in demyelinated layers. These findings suggest that activated microglia expressing TMEM119 and GLUT5, but not P2RY12, are associated with apoptosis of oligodendrocytes in the leading edge of Baló's concentric lesions with DO, whereas TMEM119-, GLUT5- and P2RY12-positive microglia with ramified morphology are associated with myelin preservation in concentric lesions without DO in Baló's disease and NMOSD. These two types of microglia appear to play distinct roles in the formation of concentric lesions.

We conducted a multicenter, randomized, double-blind, placebo-controlled prospective trial examining a supplement containing ferulic acid and Angelica archangelica extract (Feru-guard ®) for mild cognitive impairment (MCI). In the intention-to-treat population, Mini-Mental State Examination (MMSE) scores were significantly better at 24 weeks (p = 0.041) in the active group. In the per protocol population, MMSE was significantly better in the active group at 24 weeks (p = 0.008), and mixed effect models for repeated measures (MMRM) showed significant difference (p = 0.016). ADAS-Jcog was significantly better at 24 (p = 0.035) and 48 weeks (p = 0.015) in the active group, and MMRM was significant (p = 0.031). Thus, Feru-guard ® may be useful for MCI.

Pathological aggregates of tau proteins accumulate in the brains of neurodegenerative tauopathies including Alzheimer’s disease and frontotemporal lobar degeneration (FTLD-tau). Although immunotherapies of these disorders against tau are emerging, it is unknown whether nasal delivery, which offers many benefits over traditional approaches to vaccine administration, is effective or not for tauopathy. Here, we developed vaccination against a secreted form of pathological tau linked to FTLD-tau using a Sendai virus (SeV) vector infectious to host nasal mucosa, a key part of the immune system. Tau vaccines given as nasal drops induced tissue tau-immunoreactive antibody production and ameliorated cognitive impairment in FTLD-tau model mice. In vivo imaging and postmortem neuropathological assays demonstrated the suppression of phosphorylated tau accumulation, neurotoxic gliosis, and neuronal loss in the hippocampus of immunized mice. These findings suggest that nasal vaccine delivery may provide a therapeutic opportunity for a broad range of populations with human tauopathy., 認知症に対する点鼻ワクチンの開発 --遺伝子治療による免疫療法と分子イメージング--. 京都大学プレスリリース. 2020-03-26.

Extracts from Huperzia serrata (HS) function as a cholinesterase inhibitor and a glutamic acid receptor antagonist. We tested a supplement containing HS extracts, curcumin, and others in dementia patients and individuals with mild cognitive impairment (MCI) in an open label study. Most patients with Alzheimer's disease, dementia with Lewy bodies, and MCI individuals exhibited improvements in cognitive functions, as assessed by the Alzheimer's Disease Assessment Scale-cognitive subscale Japanese version. The scores were significantly improved at 6-12 weeks compared with baseline scores (p = 0.007) and at 22-28 weeks (p = 0.004). Thus, this supplement may be administered to dementia patients as well as MCI individuals.

With the objective to improve the amyloid-β (Aβ) targeting immunotherapy, we investigated the safety and efficacy of an oral vaccine with recombinant adeno-associated virus vector carrying a signal sequence and Aβ1-43 cDNA (rAAV/Aβ) in old non-human primates, 12 African green and 10 cynomolgus monkeys. The enteric-dissolving coated capsules containing rAAV/Aβ were orally administered once or twice, then monkeys' conditions were carefully observed with complete blood count and laboratory examinations of the sera. General conditions, food intake, water intake, stool conditions, body weight changes, and menstruation cycles were not significantly altered, and laboratory tests and pathological examinations of the systemic organs were unremarkable. Pathological examinations of the brain showed significant reduction of the amyloid plaque burden and intracellular Aβ without inflammatory or hemorrhagic changes in the brain. However, soluble Aβ and some Aβ oligomers were increased in rAAV-treated monkey brains without changes of the neuronal density and vascular amyloidosis. Thus, this vaccine seems to be safe in general, but we must be cautious about the increase of Aβ oligomers after vaccination. This vaccine may be recommended at a very early stage of Alzheimer's disease when little amyloid is deposited.

Huperzia serrata has been used as a Chinese folk medicine for many years. It contains huperzine A, which has a protective effect against memory deficits in animal models; however, it is unclear if H. serrata extract exerts any effects in Alzheimer’s disease (AD) models. We used H. serrata collected in Japan and determined its huperzine A content using HPLC. We determined its inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activity. H. serrata extract (30 mg/kg/day) and donepezil (10 mg/kg/day) were orally administrated for 7 days. After repeated administration, we performed the Y-maze and passive avoidance tests. H. serrata extract contained 0.5% huperzine A; H. serrata extract inhibited AChE, but not BuChE. H. serrata extract ameliorated cognitive function in mice. These results indicate that Japanese H. serrata extract ameliorates cognitive function deficits by inhibiting AChE. Therefore, H. serrata extract may be valuable for the prevention or treatment of dementia in AD.

The truncated tau protein is a component of the neurofibrillary tangles found in the brains with tauopathies. However, the molecular mechanisms by which the truncated tau fragment causes neurodegeneration remain unknown. Tau pathology was recently suggested to spread through intercellular propagation, and required the formation of 'prion-like' species. We herein identified a new fragment of the tau protein that consisted of four binding domains and a C-terminal tail (Tau-CTF24), but lacked the N-terminal projection domain, and found that it increased with aging in tauopathy model mice (Tg601). Tau-CTF24-like fragments were also present in human brains with tauopathies. A mass spectroscopic analysis revealed that Tau-CTF24 was cleaved behind R242. The digestion of full-length tau (Tau-FL) by calpain produced Tau-CTF24 in vitro and calpain activity increased in old Tg601. Recombinant Tau-CTF24 accelerated heparin-induced aggregation and lost the ability to promote microtubule assembly. When insoluble tau from diseased brains or aggregated recombinant tau was introduced as seeds into SH-SY5Y cells, a larger amount of insoluble tau was formed in cells overexpressing Tau-CTF24 than in those overexpressing Tau-FL. Furthermore, lysates containing the Tau-CTF24 inclusion propagated to naive tau-expressing cells more efficiently than those containing the Tau-FL inclusion. Immunoblot and confocal microscopic analyses revealed that aggregated Tau-CTF24 bound to cells more rapidly and abundantly than aggregated Tau-FL. Our results suggest that Tau-CTF24 contributes to neurodegeneration by enhancing prion-like propagation as well as deteriorating the mechanisms involved in microtubule function.

The imbalance between ß-amyloid (Aß) generation and clearance plays a fundamental role in the pathogenesis of Alzheimer’s disease (AD). The sporadic form of AD is characterized by an overall impairment in Aß clearance. Immunotherapy targeting Aß clearance is believed to be a promising approach and is under active clinical investigation. Autophagy is a conserved pathway for degrading abnormal protein aggregates and is crucial for Aß clearance. We previously reported that oral vaccination with a recombinant AAV/Aß vaccine increased the clearance of Aß from the brain and improved cognitive ability in AD animal models, while the underlying mechanisms were not well understood. In this study, we first demonstrated that oral vaccination with rAAV/Aß decreased the p62 level and up-regulated the LC3B-II/LC3B-I ratio in APP/PS1 mouse brain, suggesting enhanced autophagy. Further, inhibition of the Akt/mTOR pathway may account for autophagy enhancement. We also found increased anti-Aß antibodies in the sera of APP/PS1 mice with oral vaccination, accompanied by elevation of complement factors C1q and C3 levels in the brain. Our results indicate that autophagy is closely involved in oral vaccination-induced Aß clearance, and modulating the autophagy pathway may be an important strategy for AD prevention and intervention.

Active and passive immunization of Alzheimer model mice with Aβ showed clearance of aggregated amyloid β deposits and improved memory and learning. Although human trial was halted because of autoimmune encephalitis, the trial revealed that immunization with Aβ also deleted amyloid deposits in humans without clinical benefit. On these proof of concept, several clinical trials using monoclonal antibodies are on-going. Although solanezumab which recognizes Aβ monomer turned out ineffective in the primary endpoint, it showed significant beneficial effect in mild AD cases in the secondary outcome. Solanezumab is now on a large scale phase III trial in mild AD cases in the world. If it turns out to be effective, it will be the first disease modifying drug for AD in a few years. However, since monoclonal antibodies are extremely expensive, less expensive and long acting active immunization will be widely accepted. More effective and sophisticated vaccines such as DNA vaccine and recombinant viral vaccines will be utilized in future.

Cerebrospinal fluid (CSF) of clinically definite Japanese MS patients were studied in Japan as well as in two laboratories in Europe and U.S.A. We confirmed previous findings of 1) lower incidence of elevated IgG and IgG/total protein ratio, 2) lower incidence of oligoclonal IgG bands, and 3) lower incidence of elevated measles antibodies in the CSF in Japanese MS. Japanese MS patients also displayed lower incidences of elevated IgG/albumin ratio and CSF IgG/albumin index, and of elevated antibodies to other viruses. There were also marked differences between “active” MS and “inactive” MS. In “active” MS the CSF findings were similar to western MS. In “inactive” MS almost no immunological abnormalities were seen in the CSF, suggesting an immunological “burn-out” in remission in Japanese MS.

SummaryNeuropathological studies were done on our 6 cases of multiple sclerosis including a classical MS and 5 Devic type MS. The latter 5 cases showed recurrent transverse myelopathy, severe visual impairment and some brainstem signs. Pathologically main lesions were present in the spinal cord and optic nerve. The gray matter was also frequently affected in the spinal cord. The lesions were characterized by severe demyelination with tissue necrosis, poor repair by fibrous astrocytes, and lack of inflammatory cells even in the recent severe lesions where fresh hemorrhages were often present. These lesions were also present in the brainstem tegmentum and cerebral white matter to a lesser extent, which were almost limited to the periventricular regions. In some cases lesions characteristic to the classical MS were combined in the cerebrum and brainstem.From the review of autopsy cases reported in Japan between 1955 and 1980 we collected 17 cases of classical MS, 25 cases of Devic type MS in which severe necrotic lesions were almost restricted to optic nerve and spinal cord, and 43 cases of combined form. The classical cases showed longer duration, male predominace and chronic progressive course. The Devic form showed female predominace, shorter duration and remitting course.From these findings we abstracted the following characteristic features of Japanese MS; 1)lower incidence of classical MS and higher incidence of Devic type MS,2)preferential occurrence of lesions in the optic nerve and spinal cord,3)necrotizing lesions with occasional cavity formation not only in the spinal cord and optic nerve but also in the cerebrum,4)poor gliosis, and5)poor perivascular cuffing in the necrotic form.The difference from western MS is probably on the genetic back ground.

488 Oriental cases of multiple sclerosis (MS) were collected from 8 neurologists participating to this Asian MS Workshop from 6 Asian countries, and 10 Japanese neurologists in Japan, and 177 Hungarian cases from Pecs, by using the standardized data coding sheet and the same diagnostic criteria. Comparison of the clinical picture between the Asian (A) series and Hungarian (H) series revealed similar natural history such as sex ratio, age of onset, mode of onset and clinical course. Some clinical differences, as reported from the previous comparative studies, were confirmed between the 2 series. There was a greater incidence of visual loss at onset and severe visual disability at the time of last examination in the A series than in the H series. Acute transverse myelopathy, especially that of recurrent form, was more common among Asian cases than among Hungarians. Clinical form with optic-spinal predominance was more common among Asian cases. On the other hand, ataxia was less frequent in the A than in the H series. These findings are interpreted to suggest a greater incidence of severe optic nerve and spinal cord involvement among Oriental MS patients as compared with Caucasians, probably due to the modification by constitutional differences.