Journal
JOURNAL OF NEUROSCIENCE RESEARCH
Volume 75, Issue 1, Pages 12-24Publisher
WILEY-LISS
DOI: 10.1002/jnr.10834
Keywords
transgenic mice; Alzheimer's disease; FE65; beta amyloid precursor protein; Morris water maze; passive avoidance; alternative translation
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Funding
- NIA NIH HHS [AG19711, AG 15645, AG05136-19] Funding Source: Medline
- NATIONAL INSTITUTE ON AGING [R01AG019711, R03AG015645] Funding Source: NIH RePORTER
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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 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. (C) 2003 Wiley-Liss, Inc.
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