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 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.

[1]  R. Malinow,et al.  APP Processing and Synaptic Function , 2003, Neuron.

[2]  Vincent F. Castellucci,et al.  An activity-dependent switch to cap-independent translation triggered by eIF4E dephosphorylation , 2003, Nature Neuroscience.

[3]  C. Shaw,et al.  Expression of the Fe65 adapter protein in adult and developing mouse brain , 2002, Neuroscience.

[4]  D. Selkoe.  Alzheimer's Disease Is a Synaptic Failure , 2002, Science.

[5]  M. Kozak,et al.  Pushing the limits of the scanning mechanism for initiation of translation , 2002, Gene.

[6]  Christopher K. Glass,et al.  Exchange of N-CoR Corepressor and Tip60 Coactivator Complexes Links Gene Expression by NF-κB and β-Amyloid Precursor Protein , 2002, Cell.

[7]  A. Lichtman,et al.  Evaluation of CB1 receptor knockout mice in the Morris water maze. , 2002, The Journal of pharmacology and experimental therapeutics.

[8]  R. Nicoll,et al.  Endocannabinoid Signaling in the Brain , 2002, Science.

[9]  Q. Hu,et al.  A candidate molecular mechanism for the association of an intronic polymorphism of FE65 with resistance to very late onset dementia of the Alzheimer type. , 2002, Human molecular genetics.

[10]  Joe Z Tsien,et al.  Deficient Neurogenesis in Forebrain-Specific Presenilin-1 Knockout Mice Is Associated with Reduced Clearance of Hippocampal Memory Traces , 2001, Neuron.

[11]  Thomas C. Südhof,et al.  A Transcriptively Active Complex of APP with Fe65 and Histone Acetyltransferase Tip60 , 2001, Science.

[12]  P. Greengard,et al.  The Alzheimer Amyloid Precursor Protein (APP) and Fe65, an APP-Binding Protein, Regulate Cell Movement , 2001, The Journal of cell biology.

[13]  M. Sudol,et al.  The β-Amyloid Precursor Protein APP Is Tyrosine-phosphorylated in Cells Expressing a Constitutively Active Form of the Abl Protoncogene* , 2001, The Journal of Biological Chemistry.

[14]  D. Selkoe.  Alzheimer's disease: genes, proteins, and therapy. , 2001, Physiological reviews.

[15]  Ted Abel,et al.  Molecular mechanisms of memory acquisition, consolidation and retrieval , 2001, Current Opinion in Neurobiology.

[16]  T. Russo,et al.  The β-Amyloid Precursor Protein Functions as a Cytosolic Anchoring Site That Prevents Fe65 Nuclear Translocation* , 2001, The Journal of Biological Chemistry.

[17]  F. Pasquier,et al.  A FE65 polymorphism associated with risk of developing sporadic late-onset Alzheimer's disease but not with Aβ loading in brains , 2000, Neuroscience Letters.

[18]  N. Sonenberg,et al.  Internal ribosome initiation of translation and the control of cell death. , 2000, Trends in genetics : TIG.

[19]  A. Sachs.  Cell Cycle–Dependent Translation Initiation IRES Elements Prevail , 2000, Cell.

[20]  S. Cornelis,et al.  Identification and characterization of a novel cell cycle-regulated internal ribosome entry site. , 2000, Molecular cell.

[21]  Joseph L Goldstein,et al.  Regulated Intramembrane Proteolysis A Control Mechanism Conserved from Bacteria to Humans , 2000, Cell.

[22]  S. Bressler,et al.  Alternatively spliced isoforms of FE65 serve as neuron‐specific and non‐neuronal markers , 1999, Journal of neuroscience research.

[23]  B. Strooper,et al.  Presenilins: molecular switches between proteolysis and signal transduction , 1999, Trends in Neurosciences.

[24]  R. Tanzi,et al.  hFE65L Influences Amyloid Precursor Protein Maturation and Secretion , 1999, Journal of neurochemistry.

[25]  Louis J Muglia,et al.  Calcium-Stimulated Adenylyl Cyclase Activity Is Critical for Hippocampus-Dependent Long-Term Memory and Late Phase LTP , 1999, Neuron.

[26]  P. Greengard,et al.  Regulation of β-Amyloid Secretion by FE65, an Amyloid Protein Precursor-binding Protein* , 1999, The Journal of Biological Chemistry.

[27]  J. Borg,et al.  Interaction of Cytosolic Adaptor Proteins with Neuronal Apolipoprotein E Receptors and the Amyloid Precursor Protein* , 1998, The Journal of Biological Chemistry.

[28]  M. Picciotto,et al.  Using knockout and transgenic mice to study neurophysiology and behavior. , 1998, Physiological reviews.

[29]  S. Bressler,et al.  The human FE65 gene: genomic structure and an intronic biallelic polymorphism associated with sporadic dementia of the Alzheimer type , 1998, Human Genetics.

[30]  T. Russo,et al.  Fe65 and the protein network centered around the cytosolic domain of the Alzheimer's β‐amyloid precursor protein , 1998, FEBS letters.

[31]  T. Russo,et al.  The Fe65 Adaptor Protein Interacts through Its PID1 Domain with the Transcription Factor CP2/LSF/LBP1* , 1998, The Journal of Biological Chemistry.

[32]  T. Russo,et al.  Fe65L2: a new member of the Fe65 protein family interacting with the intracellular domain of the Alzheimer's beta-amyloid precursor protein. , 1998, The Biochemical journal.

[33]  M. Sudol,et al.  The WW Domain of Neural Protein FE65 Interacts with Proline-rich Motifs in Mena, the Mammalian Homolog of DrosophilaEnabled* , 1997, The Journal of Biological Chemistry.

[34]  P. Schwartzkroin,et al.  Evidence for p53-Mediated Modulation of Neuronal Viability , 1996, The Journal of Neuroscience.

[35]  S. Younkin,et al.  Correlative Memory Deficits, Aβ Elevation, and Amyloid Plaques in Transgenic Mice , 1996, Science.

[36]  S. Bressler,et al.  cDNA cloning and chromosome mapping of the human Fe65 gene: interaction of the conserved cytoplasmic domains of the human beta-amyloid precursor protein and its homologues with the mouse Fe65 protein. , 1996, Human molecular genetics.

[37]  R. Tanzi,et al.  Association of a novel human FE65-like protein with the cytoplasmic domain of the beta-amyloid precursor protein. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[38]  M. Staufenbiel,et al.  Electrophoretic Separation of βA4 Peptides (1–40) and (1–42) , 1996 .

[39]  Joseph W. Harding,et al.  Effects of discrete kainic acid-induced hippocampal lesions on spatial and contextual learning and memory in rats , 1996, Brain Research.

[40]  R. Palmiter,et al.  Targeted disruption of the tyrosine hydroxylase gene reveals that catecholamines are required for mouse fetal development , 1995, Nature.

[41]  Thomas Rülicke,et al.  Behavioral and anatomical deficits in mice homozygous for a modified β-amyloid precursor protein gene , 1994, Cell.

[42]  J. Roder,et al.  Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[43]  Yamamura Ken-ichi,et al.  Efficient selection for high-expression transfectants with a novel eukaryotic vector , 1991 .

[44]  H. Niwa,et al.  Efficient selection for high-expression transfectants with a novel eukaryotic vector. , 1991, Gene.

[45]  T. Russo,et al.  A rat brain mRNA encoding a transcriptional activator homologous to the DNA binding domain of retroviral integrases. , 1991, Nucleic acids research.

[46]  R. Lillie,et al.  Manual of Histologic and Special Staining Techniques , 1958 .

[47]  C. Glass,et al.  Exchange of N-CoR corepressor and Tip60 coactivator complexes links gene expression by NF-kappaB and beta-amyloid precursor protein. , 2002, Cell.

[48]  U. Hansen,et al.  Fe65, a ligand of the Alzheimer's beta-amyloid precursor protein, blocks cell cycle progression by down-regulating thymidylate synthase expression. , 2002, The Journal of biological chemistry.

[49]  J. Kornhuber,et al.  Improved electrophoretic separation and immunoblotting of beta‐amyloid (Aβ) peptides 1–40, 1–42, and 1–43 , 1997, Electrophoresis.

[50]  M. Staufenbiel,et al.  Electrophoretic separation of betaA4 peptides (1-40) and (1-42). , 1996, Analytical biochemistry.