Isoform-Specific Knockout of FE65 Leads to Impaired Learning and Memory

Baiping Wang, Qubai Hu, Mark G. Hearn, Kimiko Shimizu, Carol B. Ware, Dennis H. Liggitt, Lee Way Jin, Bethany H. Cool, Daniel R. Storm, George M. Martin*

*この論文の責任著者

研究成果: ジャーナルへの寄稿学術論文査読

63 被引用数 (Scopus)

抄録

FE65 is a multimodular adapter protein that is expressed predominantly in brain. Its C-terminal phosphotyrosine interaction domain (PID) binds to the intracellular tail of the β-amyloid precursor protein (βPP), a protein of central importance to the pathogenesis of dementias of the Alzheimer type. To study the physiological functions of FE65, we generated a line of FE65 knockout mice via gene targeting. By Western analysis with a panel of FE65-specific antibodies, we demonstrate that the 97-kDa full-length FE65 (p97) was ablated in the mutant mice, and that a previously undescribed FE65 isoform with apparent molecular mass of 60 kDa (p60) was expressed in both wild-type and mutant mice. p60 had a truncated N-terminus and was likely to be generated through alternative translation. Expressions of the two isoforms appeared to be brain region distinct and age dependent. The p97FE65-/- mice were viable and showed no obvious physical impairments or histopathological abnormalities. However, p97FE65-/- and p97FE65+/- mice exhibited poorer performances than wild-type mice on a passive avoidance task when tested at 14 months (P < .05). p97FE65-/- mice at 14 months also exhibited impaired hidden-platform acquisition (P < .05) and a severe reversal-learning deficit (P < .002) but normal visual-platform acquisition in the Morris water maze tests. Probe trials confirmed impairments in p97FE65-/- mice in relearning of new spatial information, suggesting a hippocampus-dependent memory-extinction deficit. Reduced secretion of Aβ peptides was observed in primary neuronal cultures of hybrids of p97FE65 -/-/βPP transgenic (Tg2576) mice. These studies suggest an important and novel function of FE65 in learning and memory.

本文言語英語
ページ(範囲)12-24
ページ数13
ジャーナルJournal of Neuroscience Research
75
1
DOI
出版ステータス出版済み - 2004/01/01

ASJC Scopus 主題領域

  • 細胞および分子神経科学

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