JSN-ISN Joint Symposium
神経変性疾患解明に向けた融合戦略 |
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| JI-1
Identification of KLC1E as an Abeta accumulation modifier in Alzheimer's disease：a novel approach to complex disease by transcriptome analysis of distinct mouse strains
Morihara Takashi
大阪大学
Though Abeta accumulation in brain is the main pathology of AD, its mechanisms in sporadic AD are largely unknown. To identify the gene which control Abeta accumulation, we analyzed distinct mouse strains by transcriptomics. We identified kinesin light chain-1 splice variant E（KLC1E）as Abeta accumulation modifier（Morihara et.al. PNAS 2014）. We believed this combination；mice and transcriptomics overcome the difficulties in human genetic studies including neurodegenerative diseases and increase the statistical power significantly.
We prepared APP Tg mice with mixed genetic backgrounds. APP Tg mice（Tg2576）by crossing onto three different mouse strains. Abeta accumulation levels in mice with DBA/2 rich genetic backgrounds were drastically lower. To identify the gene（s）which control Abeta accumulation, we performed transcriptomics in the mouse brains and identified Klc1E. We examined whether the findings in mice can be translated to humans. The levels of KLC1E mRNA were elevated in AD in human brain and lymphocyte. To address the effect of KLC1E directly, we knockdown KLC1E in SH-SY5Y and observed the decrease of Abeta production. Multiple disciplines；mouse transcript, mouse genetic, human transcript and functional analysis demonstrated that KLC1E control Aβ pathology in AD.
KLC1 is a key molecule of intracellular trafficking. AD related genes identified by recent huge scale GWASs also include many trafficking genes. These suggested that disruption of trafficking, which has been thought to be a downstream of AD pathology, is also a cause of AD. |
| JI-2
Natural and training-induced brain plasticity during the prodromal phase of Alzheimer's disease
Belleville Sylvie
Psychology Department of University of Montreal, Research Center of the institut Universitaire de Gériatrie de Montréal
It is now well agreed that the cascade of events that leads to Alzheimer's disease（AD）is initiated many years prior to the time at which patients currently meet critera for dementia. In this presentation, I will present a set of studies indicating that processes of compensation and plasticity are extremely active during the prodromal phase of AD and that they can be increased with targeted brain-training strategies. Brain plasticity refers to the structural and functional neural changes that occur in response to external stimulations or diseases. Brain plasticity is most often adaptative. When it responds to a negative event and is associated with good or better performance, it is said to have a compensatory role. Brain imaging can be used as a way to measure and better understand the compensation processes that naturally occur in the early stages of AD and following therapeutic interventions. In a first set of studies, I will use fMRI to show that older adults with mild cognitive impairment have larger brain activation than healthy in brain regions when performing episodic memory or working memory tasks and that there is a breakdown of this hyperactivation as patients progress to dementia. I will also show that hyperactivation occurs in structurally impaired brain regions suggesting that increased brain recruitment may reflect the brain's attempt to compensate for the neural loss caused by the disease. In a second set of studies, I will argue that cognitive training can induce processes of plasticity and compensation in early AD. I will show that training results in increased activation of brain regions during task performance but here, increased activation occurs in an alternative network of functionally intact brain regions. |
| JI-3
Laminin in neurodegeneration and cerebral vascular integrity
Chen Zu-Lin
Laboratory of Neurobiology and Genetics, The Rockefeller University, New York USA
Excitotoxicity is the main mechanism underlying neuronal death in stroke, anoxia, and seizure. The extracellular serine protease tissue plasminogen activator（tPA）and its zymogen substrate plasminogen are critical to excitotoxic neuronal death because mice deficient in either of these genes are resistant to excitotoxic neurodegeneration. Further study showed that the tPA/plasmin proteolytic cascade participates in excitotoxic neuronal death by degrading the extracellular matrix protein laminin. To further investigate the mechanism by which laminin participates in neuronal cell death, we knocked out neuronal laminin γ1 expression in the hippocampus using cell type-specific conditional knockout technique. Laminin γ1 knockout（KO）mice are resistant to kainate-induced neuronal cell death. We then analyzed kainate（KA）receptor expressions in laminin γ1 knockout mice, and revealed that they had similar basal expression of KA receptors as wild type mice, but after KA injection, KA1 subunit levels increased in control mice but were unchanged in laminin γ1 KO mice. KA1 levels in tPA KO mice were also unchanged after KA, indicating that both tPA and laminin were necessary for KA1 up-regulation after KA injection. Infusion of plasmin-digested laminin-1 into the hippocampus of laminin γ1 or tPA KO mice restored KA1 up-regulation and KA-induced neuronal degeneration. Interfering with KA1 function with a specific anti-KA1 antibody protected against KA-induced neuronal death both in vitro and in vivo. Our study revealed a novel pathway for neurodegeneration involving proteolysis of the ECM and KA1 receptor subunit up-regulation. Glia cells also express laminin and may contribute to the integrity of cerebral vascular wall, to investigate the functional significance of astrocytic laminin, we knocked out laminin γ1 in astrocytes. These KO mice exhibit impaired vascular smooth muscle differentiation leading to cerebral hemorrhage. Thus our studies revealed the role of neuronal laminin in neurodegeneration and astrocytic laminin in cerebral vascular integrity. | | | |
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