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

Research output: Contribution to journalArticle

56 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)12-24
Number of pages13
JournalJournal of Neuroscience Research
Volume75
Issue number1
DOIs
StatePublished - Jan 1 2004
Externally publishedYes

Fingerprint

Protein Isoforms
Learning
Reversal Learning
Phosphotyrosine
Protein Precursors
Gene Targeting
Amyloid beta-Protein Precursor
Memory Disorders
Brain
Knockout Mice
Transgenic Mice
Tail
Hippocampus
Alzheimer Disease
Proteins
Peptides
Water
Antibodies

Keywords

  • Alternative translation
  • Alzheimer's disease
  • Beta amyloid precursor protein
  • FE65
  • Morris water maze
  • Passive avoidance
  • Transgenic mice

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Wang, B., Hu, Q., Hearn, M. G., Shimizu, K., Ware, C. B., Liggitt, D. H., ... Martin, G. M. (2004). Isoform-Specific Knockout of FE65 Leads to Impaired Learning and Memory. Journal of Neuroscience Research, 75(1), 12-24. https://doi.org/10.1002/jnr.10834

Isoform-Specific Knockout of FE65 Leads to Impaired Learning and Memory. / Wang, Baiping; Hu, Qubai; Hearn, Mark G.; Shimizu, Kimiko; Ware, Carol B.; Liggitt, Dennis H.; Jin, Lee-Way; Cool, Bethany H.; Storm, Daniel R.; Martin, George M.

In: Journal of Neuroscience Research, Vol. 75, No. 1, 01.01.2004, p. 12-24.

Research output: Contribution to journalArticle

Wang, B, Hu, Q, Hearn, MG, Shimizu, K, Ware, CB, Liggitt, DH, Jin, L-W, Cool, BH, Storm, DR & Martin, GM 2004, 'Isoform-Specific Knockout of FE65 Leads to Impaired Learning and Memory', Journal of Neuroscience Research, vol. 75, no. 1, pp. 12-24. https://doi.org/10.1002/jnr.10834
Wang, Baiping ; Hu, Qubai ; Hearn, Mark G. ; Shimizu, Kimiko ; Ware, Carol B. ; Liggitt, Dennis H. ; Jin, Lee-Way ; Cool, Bethany H. ; Storm, Daniel R. ; Martin, George M. / Isoform-Specific Knockout of FE65 Leads to Impaired Learning and Memory. In: Journal of Neuroscience Research. 2004 ; Vol. 75, No. 1. pp. 12-24.
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