Behavioral Disturbances without Amyloid Deposits in Mice Overexpressing Human Amyloid Precursor Protein with Flemish (A692G) or Dutch (E693Q) Mutation

The contribution of mutations in the amyloid precursor protein (APP) gene known as Flemish (APP/A692G) and Dutch (APP/E693Q) to the pathogenesis of Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis of the Dutch type, respectively, was studied in transgenic mice that overexpress the mutant APP in brain. These transgenic mice showed the same early behavioral disturbances and defects and increased premature death as the APP/London (APP V717I), APP/Swedish (K670N, M671L), and other APP transgenic mice described previously. Pathological changes included intense glial reaction, extensive microspongiosis in the white matter, and apoptotic neurons in select areas of the brain, while amyloid deposits were absent, even in mice over 18 months of age. This contrasts with extensive amyloid deposition in APP/London transgenic mice and less pronounced amyloid deposition in APP/Swedish transgenic mice generated identically. It demonstrated, however, that the behavioral deficiencies and the pathological changes in brain resulting from an impaired neuronal function are caused directly by APP or its proteolytic derivative(s). These accelerate or impinge on the normal process of aging and amyloid deposits per se are not essential for this phenotype.

[1]  Y. Christen,et al.  Alzheimer’s Disease: Lessons from Cell Biology , 2011, Research and Perspectives in Alzheimer’s Disease.

[2]  D. Moechars,et al.  Premature death in transgenic mice that overexpress a mutant amyloid precursor protein is preceded by severe neurodegeneration and apoptosis , 1999, Neuroscience.

[3]  R. Nicoll,et al.  Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[4]  Veerle Baekelandt,et al.  Early Phenotypic Changes in Transgenic Mice That Overexpress Different Mutants of Amyloid Precursor Protein in Brain* , 1999, The Journal of Biological Chemistry.

[5]  C. Fairburn,et al.  Natural history of behavioural changes and psychiatric symptoms in Alzheimer's disease , 1999, British Journal of Psychiatry.

[6]  F. van Leuven,et al.  Aggressive behaviour in transgenic mice expressing APP is alleviated by serotonergic drugs , 1998, Neuroreport.

[7]  B. Sommer,et al.  Neuron loss in APP transgenic mice , 1998, Nature.

[8]  C. Broeckhoven,et al.  Flemish and Dutch Mutations in Amyloid β Precursor Protein Have Different Effects on Amyloid β Secretion , 1998, Neurobiology of Disease.

[9]  B. Strooper,et al.  Transgenic mice expressing an α-secretion mutant of the amyloid precursor protein in the brain develop a progressive CNS disorder , 1998, Behavioural Brain Research.

[10]  A. Hofman,et al.  Presenile Alzheimer dementia characterized by amyloid angiopathy and large amyloid core type senile plaques in the APP 692Ala→Gly mutation , 1998, Acta Neuropathologica.

[11]  L. Mucke,et al.  Amyloid Protein Precursor Stimulates Excitatory Amino Acid Transport , 1998, The Journal of Biological Chemistry.

[12]  B. Sommer,et al.  Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[13]  G. Ruvkun,et al.  The genetics of aging. , 1997, Annual review of genomics and human genetics.

[14]  R. Wurtman,et al.  Neuronal Expression of β-Amyloid Precursor Protein Alzheimer Mutations Causes Intracellular Accumulation of a C-terminal Fragment Containing Both the Amyloid β and Cytoplasmic Domains* , 1997, The Journal of Biological Chemistry.

[15]  J. Buxbaum,et al.  Characterization of New Polyclonal Antibodies Specific for 40 and 42 Amino Acid-Long Amyloid β Peptides: Their Use to Examine the Cell Biology of Presenilins and the Immunohistochemistry of Sporadic Alzheimer’s Disease and Cerebral Amyloid Angiopathy Cases , 1997, Molecular medicine.

[16]  L. Walker,et al.  Animal models of cerebral β-amyloid angiopathy , 1997, Brain Research Reviews.

[17]  Jan-Fang Cheng,et al.  Functional screening of 2 Mb of human chromosome 21q22.2 in transgenic mice implicates minibrain in learning defects associated with Down syndrome , 1997, Nature Genetics.

[18]  D. Selkoe,et al.  Evidence that the 42- and 40-amino acid forms of amyloid beta protein are generated from the beta-amyloid precursor protein by different protease activities. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[19]  R. Roos,et al.  Potential for imaging cerebral amyloid deposits using 123I-labelled serum amyloid P component and SPET. , 1996, Nuclear medicine communications.

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

[21]  R. Roos,et al.  Hereditary Cerebral Hemorrhage with Amyloidosis‐Dutch Type (HCHWA‐D): I ‐ A Review of Clinical, Radiologic and Genetic Aspects , 1996, Brain pathology.

[22]  B. Strooper,et al.  801 Expression in brain of Amyloid Precursor Protein mutated in the α-secretase site, causes disturbed behavior, neuronal degeneration and premature death in transgenic mice , 1996, Neurobiology of Aging.

[23]  D. Borchelt,et al.  Age-related CNS disorder and early death in transgenic FVB/N mice overexpressing Alzheimer amyloid precursor proteins , 1995, Neuron.

[24]  B. de Strooper,et al.  Production of intracellular amyloid‐containing fragments in hippocampal neurons expressing human amyloid precursor protein and protection against amyloidogenesis by subtle amino acid substitutions in the rodent sequence. , 1995, The EMBO journal.

[25]  B. Greenberg,et al.  Mutant and native human β-amyloid precursor proteins in transgenic mouse brain , 1995, Neurobiology of Aging.

[26]  P. Moran,et al.  Age-related learning deficits in transgenic mice expressing the 751-amino acid isoform of human beta-amyloid precursor protein. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[27]  M. S. Goldman,et al.  Cortical petechial hemorrhage, leukoencephalopathy, and subacute dementia associated with seizures due to cerebral amyloid angiopathy. , 1995, Mayo Clinic proceedings.

[28]  L. Mucke,et al.  Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein , 1995, Nature.

[29]  T. Bliss,et al.  Memories of NMDA receptors and LTP , 1995, Trends in Neurosciences.

[30]  J. Olney,et al.  Excitotoxicity and the NMDA receptor - still lethal after eight years , 1995, Trends in Neurosciences.

[31]  C. Broeckhoven.  Genes in early onset Alzheimer's disease: Implications for AD research , 1994, Neurobiology of Aging.

[32]  S. M. Sumi,et al.  Phenotype of chromosome 14–linked familial Alzheimer's disease in a large kindred , 1994, Annals of neurology.

[33]  Robert C. Malenka,et al.  Synaptic plasticity in the hippocampus: LTP and LTD , 1994, Cell.

[34]  D. Selkoe,et al.  Mutations associated with a locus for familial Alzheimer's disease result in alternative processing of amyloid beta-protein precursor. , 1994, The Journal of biological chemistry.

[35]  D. Holtzman,et al.  Transgenic mouse brain histopathology resembles early Alzheimer's disease , 1994, Annals of neurology.

[36]  D. Walsh,et al.  Effects of the mutations Glu22 to Gln and Ala21 to Gly on the aggregation of a synthetic fragment of the Alzheimer's amyloid β/A4 peptide , 1993, Neuroscience Letters.

[37]  Toru Shimizu,et al.  Clinical comparison of Alzheimer's disease in pedigrees with the codon 717 Val→Ile mutation in the amyloid precursor protein gene , 1993, Neurobiology of Aging.

[38]  P. Lansbury,et al.  Seeding “one-dimensional crystallization” of amyloid: A pathogenic mechanism in Alzheimer's disease and scrapie? , 1993, Cell.

[39]  R. Frackowiak,et al.  Familial Alzheimer's disease. A pedigree with a mis-sense mutation in the amyloid precursor protein gene (amyloid precursor protein 717 valine-->glycine). , 1993, Brain : a journal of neurology.

[40]  D. Selkoe,et al.  Amyloid β-peptide is produced by cultured cells during normal metabolism , 1992, Nature.

[41]  C. Cotman,et al.  Hippocampal excitatory amino acid receptors in elderly, normal individuals and those with Alzheimer's disease: Non-N-methyl-d-aspartate receptors , 1992, Neuroscience.

[42]  B. Winblad,et al.  A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N–terminus of β–amyloid , 1992, Nature Genetics.

[43]  R. Albin,et al.  Alternative excitotoxic hypotheses , 1992, Neurology.

[44]  C. Broeckhoven,et al.  Hereditary Cerebral Hemorrhage with Amyloidosis—Dutch Type: A Congophilic Angiopathy , 1991 .

[45]  T. Wisniewski,et al.  Peptides homologous to the amyloid protein of Alzheimer's disease containing a glutamine for glutamic acid substitution have accelerated amyloid fibril formation. , 1991, Biochemical and biophysical research communications.

[46]  K. Murakami,et al.  Formation of β-amyloid protein deposits in brains of transgenic mice , 1991, Nature.

[47]  N. Robakis,et al.  Exact cleavage site of Alzheimer amyloid precursor in neuronal PC-12 cells , 1991, Neuroscience Letters.

[48]  M. Pericak-Vance,et al.  Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease , 1991, Nature.

[49]  C. van Broeckhoven,et al.  Early‐onset Alzheimer's disease in 2 large Belgian families , 1991, Neurology.

[50]  R. Faull,et al.  Alzheimer's disease: Changes in hippocampal N-methyl-d-aspartate, quisqualate, neurotensin, adenosine, benzodiazepine, serotonin and opioid receptors—an autoradiographic study , 1990, Neuroscience.

[51]  C. Cotman,et al.  β-Amyloid protein increases the vulnerability of cultured cortical neurons to excitotoxic damage , 1990, Brain Research.

[52]  J. Morris,et al.  Advanced Alzheimer's disease is a risk factor for late-onset seizures. , 1990, Archives of neurology.

[53]  J. Hardy,et al.  Amyloid beta protein precursor gene and hereditary cerebral hemorrhage with amyloidosis (Dutch). , 1990, Science.

[54]  I. Lieberburg,et al.  Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. , 1990, Science.

[55]  A. Young,et al.  Excitatory amino acids and Alzheimer's disease , 1989, Neurobiology of Aging.

[56]  J. Penney,et al.  Dementia of the Alzheimer's Type: Changes in Hippocampal L‐[3H]Glutamate Binding , 1987, Journal of neurochemistry.

[57]  G. Stoppe,et al.  Behavioural Problems Associated With Dementia , 1999, Drugs & aging.

[58]  C. Broeckhoven,et al.  Alzheimer’s Disease and Hemorrhagic Stroke: Their Relationship to βA4 Amyloid Deposition , 1995 .

[59]  C. Bieberich,et al.  The Alzheimer's Aβ peptide induces neurodegeneration and apoptotic cell death in transgenic mice , 1995, Nature Genetics.

[60]  A. Hofman,et al.  Apolipoprotein E4 allele in a population–based study of early–onset Alzheimer's disease , 1994, Nature Genetics.

[61]  D. Selkoe,et al.  Normal and abnormal biology of the beta-amyloid precursor protein. , 1994, Annual review of neuroscience.

[62]  D. Price,et al.  Cellular and molecular biology of Alzheimer's disease and animal models. , 1994, Annual review of medicine.

[63]  A. Hofman,et al.  Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the β–amyloid precursor protein gene , 1992, Nature Genetics.