東邦大学理学部生物分子科学科分子医化学グループ・准教授上田 ( 石原 ) 奈津実Natsumi Ageta-IshiharaDepartment of Biomolecular Science, Faculty of Science, Toho UniversityAbstractMild cognitive impairment has been defined as an intermediate state between normal and dementia (impairment in the retention of episodic memory, etc., while not interfering with daily life). Since there is no drug therapy that can recover from dementia and improving QOL by reducing the number of patients with dementia leads to extension of healthy life expectancy, it is required to search for drug candidate molecules and establish diagnostic methods for mild cognitive impairment.We have been studying the physiological significance of the neural network formation and maintenance of the septin cytoskeleton, SEPT1-14 (Ageta-Ishihara et al., Nature Commun 2013, Nature Commun 2015, Neurochem Int 2018, Neurosci Res 2021, The Japan Neuroscience Society Young Investigator Award 2019, The Young Scientists’ Award 2020). Septin is highly expressed in brain and is recognized as a GTP-binding protein associated with neuropsychiatric disorders. To identify septin subunits involved in learning and memory, we compared immunoreactivity of SEPT1-14 in the control and tetanized sites after induction of late phase LTP (L-LTP) as a long-term memory model and found that L-LTP accompanies remodeling of the SEPT subunit. SEPT is a unique subunit that exhibits brain-specific expression and regulates cognitive ability and intelligence. For unbiased detection of neural phenotypes of Sept-deficient mice, we conducted behavioral screening followed by scrutiny for the responsible morphological and physiological anomalies. Sept-/- mice performed normally in most behavioral paradigms. Intriguingly, however, they retain memory of spatial context for 2h, but not for 24h, in the episodic memory test. SEPT-deficient neurons are largely normal in basal transmission properties and ultrastructure morphology, except for the maintenance phase of L-LTP and a significant scarcity of smooth endoplasmic reticulum (sER) in dendritic spines. SEPT depletion spares persistent spine enlargement triggered by L-LTP-inducing stimuli, while abolishing sER extension into enlarged spines. Given the fact that sER is an ― 171 ―軽度認知症治療へのタンパク質二量化操作技術の適用Application of protein dimerization engineering technology to mild dementia treatment
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