Isoform-specific knockout of FE65 leads to impaired learning and memory.
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 beta-amyloid precursor protein (betaPP), 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 Abeta peptides was observed in primary neuronal cultures of hybrids of p97FE65(-/-)/betaPP transgenic (Tg2576) mice. These studies suggest an important and novel function of FE65 in learning and memory.
Wang
Baiping
B
Department of Pathology, University of Washington, Seattle, Washington 98195-7470, USA.
Hu
Qubai
Q
Hearn
Mark G
MG
Shimizu
Kimiko
K
Ware
Carol B
CB
Liggitt
Dennis H
DH
Jin
Lee-Way
LW
Cool
Bethany H
BH
Storm
Daniel R
DR
Martin
George M
GM
D000375:Aging; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001362:Avoidance Learning; D001522:Behavior, Animal; D015152:Blotting, Northern; D015153:Blotting, Western; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D004597:Electroshock / Q000009:adverse effects; D005260:Female; D007211:Indoles / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008569:Memory Disorders / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D015394:Molecular Structure; D009043:Motor Activity / Q000235:genetics / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D011597:Psychomotor Performance; D012333:RNA, Messenger / Q000096:biosynthesis; D011930:Reaction Time; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013550:Swimming; D013997:Time Factors; D014162:Transfection; D014828:Vocalization, Animal
D016229:Amyloid beta-Peptides; C486243:Apbb1 protein, mouse; D007211:Indoles; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D020033:Protein Isoforms; D012333:RNA, Messenger; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C018588:Luxol Fast Blue MBS