認知の加齢変化 Aging of Cognition

P3-2-158 認知機能の加齢変化における神経性インスリン様シグナルの役割 Role of neural insulin-like signaling in age-related cognitive change ○田口明子1,2, 牧ノ段学3,4, 福岡屋航2, 倉田栄子2, 岸本年史4 ○Akiko Taguchi1,2, Manabu Makinodan3,4, Wataru Fukuokaya2, Eiko Kurata2, Toshifumi Kishimoto4, Gabriel Corfas3, Morris White2 宮崎大・医・神経内分泌代謝学1, ハーバード大・医・ボストン小児病院・内分泌学2, ハーバード大・医・ボストン小児病院・神経学耳鼻咽喉学3, 奈良医大・精神医学4 Div Neurology, Endocrinology, and Metabolism, Faculty of Medicine, Univ of Miyazaki, Miyazaki, Japan1, Div Endocrinology, Childrens Hospital Boston Harvard Med Sch, Boston, USA2, Div Neurology and Otolaryngology, Childrens Hospital Boston Harvard Med Sch, Boston, USA3, Dpt Psychiatry, Nara Medical University, Nara, Japan4 Aging induces changes in cellular function and is the greatest risk factor for the development of neurodegenerative disease, such as Alzheimer disease (AD). Activation of Insulin-receptor(IR) /IGF1receptor(IGF1R) signaling pathways through phosphorylation of the Insulin Receptor Substrates (IRSs) is critical for neural cell growth and survival and adult neural plasticity. By contrast, in mice, attenuation of brain IRS2 extends life span and reverses premature mortality with reduction in aggregated β-amyloid in AD model animals, suggesting that reduced neural IRS2 signaling possesses anti-aging and neuroprotective effects despite paradoxical consequences of IR/IGF1R signaling. The decline in hippocampal function to support cognition is a pathognomonic physiological change with aging, which is correlated with reduced neurogenesis in the hippocampal dentate gyrus (DG). We previously showed that IRS2 is expressed in the hippocampus including DG, however it remains unknown whether IRS2 signaling is involved in adult hippocampal neurogenesis that is associated with age-related physiological change in hippocampus-dependent cognitive function. We first examined the detailed IRS2 expression profile in the DG. Double-immunostaining for IRS2 with markers for neural stem/progenitor cells (NSPCs) demonstrated that IRS2 is expressed not only in mature neurons but also in NSPC. BrdU pulse-labeling experiments revealed that subsets of BrdU (+) cells are positive for IRS2, and the number of BrdU (+) cells is significantly increased in the DG of aged mice lacking neural IRS2 (BIrs2ko+/- and -/- ) compared to age-matched controls. With increased proliferation in the DG, the elevated number of newborn neurons was also observed in aged BIrs2ko+/- and -/- mice. These data suggested that neural IRS2 signaling negatively regulates adult hippocampal neurogenesis and may promote age-related change in hippocampus-dependent cognition.

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