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Isoform‐specific knockout of FE65 leads to impaired learning and memory
Author(s) -
Wang Baiping,
Hu Qubai,
Hearn Mark G.,
Shimizu Kimiko,
Ware Carol B.,
Liggitt Dennis H.,
Jin LeeWay,
Cool Bethany H.,
Storm Daniel R.,
Martin George M.
Publication year - 2003
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.10834
Subject(s) - gene isoform , genetically modified mouse , knockout mouse , mutant , wild type , morris water navigation task , signal transducing adaptor protein , hippocampus , amyloid precursor protein , neuroscience , transgene , gene knockin , biology , alzheimer's disease , microbiology and biotechnology , chemistry , medicine , biochemistry , receptor , signal transduction , gene , disease
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. © 2003 Wiley‐Liss, Inc.