Isoform‐specific knockout of FE65 leads to impaired learning and memory

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Abstract
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.

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