Forebrain depletion of Rheb GTPase elicits spatial memory deficits in mice

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• 作者：Neelam Shahani ; Wen-Chin Huang ; Megan Varnum ; Damon T. Page ; Srinivasa Subramaniam ; ^{ssubrama@scripps.edu}
• 关键词：Rheb ; Forebrain ; BACE1 ; Spatial memory ; Alzheimer's disease
• 刊名：Neurobiology of Aging
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：50
• 期：Complete
• 页码：134-143
• 全文大小：1642 K
• 卷排序：50

文摘

The precise molecular and cellular events responsible for age-dependent cognitive dysfunctions remain unclear. We report that Rheb (ras homolog enriched in brain) GTPase, an activator of mammalian target of rapamycin (mTOR), regulates memory functions in mice. Conditional depletion of Rheb selectively in the forebrain of mice obtained from crossing Rhebf/f and CamKIICre results in spontaneous signs of age-related memory loss, that is, spatial memory deficits (T-maze, Morris water maze) without affecting locomotor (open-field test), anxiety-like (elevated plus maze), or contextual fear conditioning functions. Partial depletion of Rheb in forebrain was sufficient to elicit memory defects with little effect on the neuronal size, cortical thickness, or mammalian target of rapamycin activity. Rheb depletion, however, increased the levels of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), a protein elevated in aging and Alzheimer's disease. Overall, our study demonstrates that forebrain Rheb promotes aging-associated cognitive defects. Thus, molecular understanding of Rheb pathway in brain may provide new therapeutic targets for aging and/or Alzheimer's disease–associated memory deficits.