公募シンポジウム１２：「認知症」病態機序解明からブレイクスルーを目指した地道な基盤研究
Symposium12 : Scientific research aiming for a major breakthrough from the biological basis of dementia |
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| 2020/9/11 16:50～17:12 Zoom B
SY12-01
アルツハイマー病への予防的介入と根治療法のために
Towards prevention and treatment of Alzheimer's disease
*斉藤 貴志1
1. 名古屋市立大学
*Takashi Saito1
1. Nagoya City Univ.
Alzheimer's disease (AD), the primary cause of dementia in the elderly, imposes a tremendous social and economic burden in the world. However, development of drugs for prevention and treatment of AD is not still solved. AD is characterized by specific pathologies which are the deposition of amyloid-β peptide (Aβ) and neurofibrillary tangles composed of microtubule-associated protein tau (Mapt). Recently, it is thought that longitudinal pathophysiological processes in neurodegenerative disorders including AD cause to be in a state of chronic neuroinflammation involving in deleterious activation of glial cells. However, the molecular, cellular and pathological mechanisms in AD are remained unclear because of the disease complexities. To make matters worse, the existing animal models of AD were not accurate or reproducible, and thus, the development of therapeutic strategies for this disease is slow. To overcome these difficulties, we developed novel mouse models. One is an amyloid precursor protein (App) knockin mouse which exhibit a robust and AD-relevant amyloidosis accompanied by a significant neuroinflammation. The other one is a humanized Tau knockin (MAPT KI) mouse expressing all isoforms of human Tau. We then generated the double KI (dKI) mice by crossing App KI with MAPT KI mice. In this symposium, we would like to introduce recent results using such model mice and share perspectives for understanding glial pathophysiology. Our final goal is to establish presymptomatic diagnostics and find the disease-modifying treatment for prevention and therapy of the disease by elucidating the molecular mechanisms for AD pathogenesis.
| | 2020/9/11 17:12～17:34 Zoom B
SY12-02
アルツハイマー病周辺症状を標的とした新たな治療戦略
Exploration of novel mechanism target for behavioral and psychological symptoms of Alzheimer's disease
*森口 茂樹1
1. 東北大学
*Shigeki Moriguchi1
1. Tohoku Univ.
ATP-sensitive K+ (KATP) channels are predominantly expressed in the brain and consist of 4 identical inward-rectifier potassium ion channel subunits (Kir6.1 or Kir6.2) and 4 identical high-affinity sulfonylurea receptor subunits (SUR1, SUR2A, or SUR2B). We previously observed that chronic-corticosterone-treated (CORT) mice exhibited enhanced anxiety-like behaviors and cued fear memory. In the present study, the protein and mRNA expression levels of Kir6.1, but not Kir6.2, were decreased in the lateral amygdala (LA) of CORT mice. Heterozygous Kir6.1-null (Kir6.1+/−) mice also showed enhanced tone (cued) fear memory and long-term potentiation (LTP) in the cortico-LA pathway compared to those in wild-type (WT) mice. However, LTP was not enhanced in the hippocampal CA1 regions of Kir6.1+/− mice. Consistent with increased cued fear memory, both Ca2+/calmodulin-dependent protein kinase II (CaMKII) and extracellular-signal-regulated kinase (ERK) activities were significantly elevated in the LAs of Kir6.1+/− mice after tone stimulation. Our results indicate that increased CaMKII and ERK activities may induce LTP in the LA in Kir6.1+/− mice, leading to aberrant cued fear memory. The changes in neural plasticity in the LA of Kir6.1+/− mice were associated with anxiety-like behaviors and may be related to the pathogenic mechanisms of anxiety disorders in human patients.
| | 2020/9/11 17:35～17:57 Zoom B
SY12-03
マウス雌雄差による認知記憶の違い
Gender differences in cognitive functions in mice
*宇野 恭介1
1. 摂南大学薬学部 機能形態学
*Kyosuke UNO1
1. Laboratory of Molecular Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University,
Shati/Nat8l is a novel N-acetyltransferase identified in the brain of mice treated with methamphetamine (METH). Shati/Nat8l mRNA is expressed in various brain areas, including the prefrontal cortex (PFC), where the expression level is higher than that in other brain regions. Shati/Nat8l overexpression in the nucleus accumbens (NAc) attenuates the pharmacological response to METH via mGluR3. We reported that the expression of Shati/Nat8l mRNA is increased following brain development in mice. These findings have suggested that Shati/Nat8l has essential roles in neuronal function. In this study, we carried out various behavioral and electrophysiological study using Shati KO mice to clarify the contribution of Shati/Nat8l on the cognitive function in mice.
We assessed the validity of behavioral test using Shati KO mice and wild type (WT) mice. Next, we prepared hippocampal slices from Shati KO and WT mice, and recorded the evoked field excitatory postsynaptic potentials and long-term potentiation (LTP) using MED64 systems.
In the open field test, Shati KO mice showed higher basal locomotor activity. Shati KO mice avoided social interaction with unfamiliar mice compared with WT mice. In the elevated plus maze test, Shati KO mice spent much longer time in open arms than WT mice. These behavioral changes were observed both male and female Shati KO mice. Interestingly, inpairment of cognitive dysfunction in the Y-maze and novel object recognition were observed only in Shati KO female mice. Furthermore, injection of adeno associated virus vector of Shati/Nat8l into hippocampal CA3 region of Shati KO ameliorated these cognitive dysfunctions in the female mice. Also, in the electrophysiology test, the LTP of Shati KO mice were significantly decreased compared with wild type mice of both male and female mice.
These results suggest that shati would be associated with cognitive function of mice and has some sexual differences.
| | 2020/9/11 17:58～18:20 Zoom B
SY12-04
アストロサイトを介したアルツハイマー病態増悪機構
Novel mechanism exacerbating Alzheimer's disease pathology through astrocytes
*照沼 美穂1
1. 新潟大学
*Miho Terunuma1
1. Niigata University
Ammonia is known as a potent neurotoxin that causes severe damages to the central nervous system. Several studies have suggested that ammonia may involve in Alzheimer's disease (AD). The excessive formation of ammonia in the brain and the elevated blood ammonia concentrations have been reported in AD patients. However, the direct evidence for a role of ammonia in the pathophysiology of AD remains unknown. We have recently found that ammonia increases the amount of mature amyloid precursor protein (APP) in astrocytes, the largest and most prevalent type of glial cells in the central nervous system, and induces amyloid beta (Aβ) production. The accumulation of mature APP was due to an inhibition in lysosomal degradation and enhanced targeting of APP to the endoplasmic reticulum were occurred where Aβ was generated. The enhanced production of Aβ in astrocytes induced by ammonia was specific to Aβ42, a principal component of senile plaques in AD patients. Our data provide a strong evidence that ammonia involves in AD pathologies by promoting the generation of Aβ42 in astrocytes.
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