Yoichiro Nishida

GLUT1 reductions exacerbate Alzheimer's disease vasculo-neuronal dysfunction and degeneration

The glucose transporter GLUT1 at the blood-brain barrier (BBB) mediates glucose transport into the brain. Alzheimers disease is characterized by early reductions in glucose transport associated with diminished GLUT1 expression at the BBB. Whether GLUT1 reduction influences disease pathogenesis remains, however, elusive. Here we show that GLUT1 deficiency in mice overexpressing amyloid β-peptide (Aβ) precursor protein leads to early cerebral microvascular degeneration, blood flow reductions and dysregulation and BBB breakdown, and to accelerated amyloid β-peptide (Aβ) pathology, reduced Aβ clearance, diminished neuronal activity, behavioral deficits, and progressive neuronal loss and neurodegeneration that develop after initial cerebrovascular degenerative changes. We also show that GLUT1 deficiency in endothelium, but not in astrocytes, initiates the vascular phenotype as shown by BBB breakdown. Thus, reduced BBB GLUT1 expression worsens Alzheimers disease cerebrovascular degeneration, neuropathology and cognitive function, suggesting that GLUT1 may represent a therapeutic target for Alzheimers disease vasculo-neuronal dysfunction and degeneration.

Depletion of Vitamin E Increases Amyloid β Accumulation by Decreasing Its Clearances from Brain and Blood in a Mouse Model of Alzheimer Disease

Increased oxidative damage is a prominent and early feature in Alzheimer disease. We previously crossed Alzheimer disease transgenic (APPsw) model mice with α-tocopherol transfer protein knock-out (Ttpa−/−) mice in which lipid peroxidation in the brain was significantly increased. The resulting double-mutant (Ttpa−/−APPsw) mice showed increased amyloid β (Aβ) deposits in the brain, which was ameliorated with α-tocopherol supplementation. To investigate the mechanism of the increased Aβ accumulation, we here studied generation, degradation, aggregation, and efflux of Aβ in the mice. The clearance of intracerebral-microinjected 125I-Aβ1–40 from brain was decreased in Ttpa−/− mice to be compared with wild-type mice, whereas the generation of Aβ was not increased in Ttpa−/−APPsw mice. The activity of an Aβ-degrading enzyme, neprilysin, did not decrease, but the expression level of insulin-degrading enzyme was markedly decreased in Ttpa−/− mouse brain. In contrast, Aβ aggregation was accelerated in Ttpa−/− mouse brains compared with wild-type brains, and well known molecules involved in Aβ transport from brain to blood, low density lipoprotein receptor-related protein-1 (LRP-1) and p-glycoprotein, were up-regulated in the small vascular fraction of Ttpa−/− mouse brains. Moreover, the disappearance of intravenously administered 125I-Aβ1–40 was decreased in Ttpa−/− mice with reduced translocation of LRP-1 in the hepatocytes. These results suggest that lipid peroxidation due to depletion of α-tocopherol impairs Aβ clearances from the brain and from the blood, possibly causing increased Aβ accumulation in Ttpa−/−APPsw mouse brain and plasma.

Genetic vitamin E deficiency does not affect MPTP susceptibility in the mouse brain

Oxidative stress is involved in the degeneration of the nigrostriatal dopaminergic system in Parkinsons disease (PD). Vitamin E (alpha‐tocopherol) is a potent antioxidant in the cell membrane that can trap free radicals and prohibit lipid peroxidation. The retention and secretion of vitamin E are regulated by alpha‐tocopherol transfer protein (TTP) in the brain and liver. Dysfunction of TTP results in systemic deficiency of vitamin E in humans and mice, and increased oxidative stress in mouse brain. In this study, we investigated the effect of vitamin E deficiency in PD development by generating an 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) mouse model of PD using TTP knockout (TTP–/–) mice. Vitamin E concentration in the brains of TTP+/– mice was half that in TTP+/+ mice, and in TTP–/– mice, was undetectable. MPTP treatment tended to decrease striatal dopamine, but the effect was comparable and not significant in any of the three genotypes. Furthermore, the extent of loss of dopaminergic cell bodies in the substantia nigra did not differ among the groups. One the other hand, oral administration of vitamin E resulted in the partial protection of striatal dopaminergic terminals against MPTP toxicity. Our results suggest that vitamin E does not play a major protective role in MPTP‐induced nigrostriatal dopaminergic neurodegeneration in the brain.

Enhanced Phospholipase A2 Group 3 Expression by Oxidative Stress Decreases the Insulin-Degrading Enzyme.

Oxidative stress has a ubiquitous role in neurodegenerative diseases and oxidative damage in specific regions of the brain is associated with selective neurodegeneration. We previously reported that Alzheimer disease (AD) model mice showed decreased insulin-degrading enzyme (IDE) levels in the cerebrum and accelerated phenotypic features of AD when crossbred with alpha-tocopherol transfer protein knockout (Ttpa -/-) mice. To further investigate the role of chronic oxidative stress in AD pathophysiology, we performed DNA microarray analysis using young and aged wild-type mice and aged Ttpa -/- mice. Among the genes whose expression changed dramatically was Phospholipase A2 group 3 (Pla2g3); Pla2g3 was identified because of its expression profile of cerebral specific up-regulation by chronic oxidative stress in silico and in aged Ttpa -/- mice. Immunohistochemical studies also demonstrated that human astrocytic Pla2g3 expression was significantly increased in human AD brains compared with control brains. Moreover, transfection of HEK293 cells with human Pla2g3 decreased endogenous IDE expression in a dose-dependent manner. Our findings show a key role of Pla2g3 on the reduction of IDE, and suggest that cerebrum specific increase of Pla2g3 is involved in the initiation and/or progression of AD.

Pure sensory infarct in the territories of anterior cerebral artery

# {#article-title-2} To the Editor: An intriguing Neuro Image suggests that an infarct in the sensory cortical homunculus resulted in a pure sensory stroke affecting only the patients leg below the knee.1 However, the infarct in the MRI is clearly in the frontal lobe and anterior to the precentral gyrus. The postcentral gyrus is the expected location of such an infarct and would explain the patients symptoms. Can the authors explain this discrepancy?

Safety and efficacy of eculizumab in Guillain-Barré syndrome: a multicentre, double-blind, randomised phase 2 trial

BACKGROUND Despite the introduction of plasmapheresis and immunoglobulin therapy, many patients with Guillain-Barré syndrome still have an incomplete recovery. Evidence from pathogenesis studies suggests the involvement of complement-mediated peripheral nerve damage. We aimed to investigate the safety and efficacy of eculizumab, a humanised monoclonal antibody against the complement protein C5, in patients with severe Guillain-Barré syndrome. METHODS This study was a 24 week, multicentre, double-blind, placebo-controlled, randomised phase 2 trial done at 13 hospitals in Japan. Eligible patients with Guillain-Barré syndrome were aged 18 years or older and could not walk independently (Guillain-Barré syndrome functional grade 3-5). Patients were randomly assigned (2:1) to receive 4 weeks of intravenous immunoglobulin plus either eculizumab (900 mg) or placebo; randomisation was done via a computer-generated process and web response system with minimisation for functional grade and age. The study had a parallel non-comparative single-arm outcome measure. The primary outcomes were efficacy (the proportion of patients with restored ability to walk independently [functional grade ≤2] at week 4) in the eculizumab group and safety in the full analysis set. For the efficacy endpoint, we predefined a response rate threshold of the lower 90% CI boundary exceeding 50%. This trial is registered with ClinicalTrials.gov, number, NCT02493725. FINDINGS Between Aug 10, 2015, and April 21, 2016, 34 patients were assigned to receive either eculizumab (n=23) or placebo (n=11). At week 4, the proportion of the patients able to walk independently (functional grade ≤2) was 61% (90% CI 42-78; n=14) in the eculizumab group, and 45% (20-73; n=5) in the placebo group. Adverse events occurred in all 34 patients. Three patients had serious adverse events: two in the eculizumab group (anaphylaxis in one patient and intracranial haemorrhage and abscess in another patient) and one in the placebo group (depression). The possibility that anaphylaxis and intracranial abscess were related to eculizumab could not be excluded. No deaths or meningococcal infections occurred. INTERPRETATION The primary outcome measure did not reach the predefined response rate. However, because this is a small study without statistical comparison with the placebo group, the efficacy and safety of eculizumab could be investigated in larger, randomised controlled trials. FUNDING The Japan Agency for Medical Research and Development, Ministry of Health, Labor and Welfare, and Alexion Pharmaceuticals.

MOLECULAR IMAGING AND TREATMENT OF ALZHEIMER’S DISEASE BY DEVELOPING AMYLOID-β OLIGOMER ANTIBODIES THAT CROSS THE BLOOD-BRAIN BARRIER

Nobuo Sanjo, Hiroya Kuwahara, Tetsuya Nagata, Yoichiro Nishida, Akiko Amano, Fumiko Furukawa, Kousei Hirata, Hiroyuki Maruoka, Makoto Nakakido, Tsumoto Kohei, Yasutaka Anraku, Kazunori Kataoka, Ichio Aoki, Etsuro Matsubara, Takami Tomiyama, Takanori Yokota, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Tokyo Medical and Dental University, Tokyo, Japan; The University of Tokyo, Tokyo, Japan; The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Innovation Center of NanoMedicine, Kawasaki, Japan; National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan; Oita University Faculty of Medicine, Oita, Japan; Osaka City University, Osaka, Japan. Contact e-mail: n-sanjo. nuro@tmd.ac.jp

Retinitis pigmentosa and macular degeneration in a patient with ataxia with isolated vitamin E deficiency with a novel c.717 del C mutation in the TTPA gene

Ataxia with isolated vitamin E deficiency (AVED) is a neurodegenerative disease caused by a mutation in the α-tocopherol transfer protein gene (TTPA). The clinical features of the disease resemble Friedreichs ataxia. However, AVED is associated with low plasma vitamin E levels, which results in compromised antioxidant function. Dysregulation of this lipid-soluble antioxidant vitamin plays a major role in the neurodegeneration observed in AVED. Some AVED patients experience decreased visual acuity. Retinitis pigmentosa is thought to be the main cause of this visual impairment. Although antioxidant levels are important for the prevention of macular degeneration, there have been no reports of macular degeneration in AVED. Here, we describe a patient with AVED with progressive macular degeneration, who carried a novel truncating mutation-c.717 del C (p.D239EfsX25)-in exon 5 of the TTPA gene. These findings suggest that this newly identified mutation results in severely low serum vitamin E levels, which may be associated with the development of retinitis pigmentosa and macular degeneration.