A Mouse Model of Amyloid β Oligomers: Their Contribution to Synaptic Alteration, Abnormal Tau Phosphorylation, Glial Activation, and Neuronal Loss In Vivo

Although amyloid β (Aβ) oligomers are presumed to cause synaptic and cognitive dysfunction in Alzheimer's disease (AD), their contribution to other pathological features of AD remains unclear. To address the latter, we generated APP transgenic mice expressing the E693Δ mutation, which causes AD by enhanced Aβ oligomerization without fibrillization. The mice displayed age-dependent accumulation of intraneuronal Aβ oligomers from 8 months but no extracellular amyloid deposits even at 24 months. Hippocampal synaptic plasticity and memory were impaired at 8 months, at which time the presynaptic marker synaptophysin began to decrease. Furthermore, we detected abnormal tau phosphorylation from 8 months, microglial activation from 12 months, astrocyte activation from 18 months, and neuronal loss at 24 months. These findings suggest that Aβ oligomers cause not only synaptic alteration but also other features of AD pathology and that these mice are a useful model of Aβ oligomer-induced pathology in the absence of amyloid plaques.

[1]  D. Selkoe,et al.  Intraneuronal Aβ42 accumulation in Down syndrome brain , 2002 .

[2]  E. Bigio,et al.  Monoclonal antibodies that target pathological assemblies of Aβ , 2007, Journal of neurochemistry.

[3]  W. Klein,et al.  Aβ Oligomer-Induced Aberrations in Synapse Composition, Shape, and Density Provide a Molecular Basis for Loss of Connectivity in Alzheimer's Disease , 2007, The Journal of Neuroscience.

[4]  Y. Imai,et al.  A novel gene iba1 in the major histocompatibility complex class III region encoding an EF hand protein expressed in a monocytic lineage. , 1996, Biochemical and biophysical research communications.

[5]  T. Morgan,et al.  Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[6]  G. Jicha,et al.  Alz‐50 and MC‐1, a new monoclonal antibody raised to paired helical filaments, recognize conformational epitopes on recombinant tau , 1997, Journal of neuroscience research.

[7]  C. Finch,et al.  Alzheimer's disease-affected brain: Presence of oligomeric Aβ ligands (ADDLs) suggests a molecular basis for reversible memory loss , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[8]  石橋 謙一.  Absence of synaptophysin near cortical neurons containing oligomer Aβ in Alzheimer's disease brain , 2006 .

[9]  P. Greengard,et al.  Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology. , 2002, The American journal of pathology.

[10]  B. Chromy,et al.  Amyloid-β peptide activates cultured astrocytes: morphological alterations, cytokine induction and nitric oxide release , 1998, Brain Research.

[11]  J. D. McGaugh,et al.  Intraneuronal Aβ Causes the Onset of Early Alzheimer’s Disease-Related Cognitive Deficits in Transgenic Mice , 2005, Neuron.

[12]  T. Matsuyama,et al.  Environmental change during postnatal development alters behaviour, cognitions and neurogenesis of mice , 2007, Behavioural Brain Research.

[13]  D. Selkoe,et al.  Natural oligomers of the amyloid-β protein specifically disrupt cognitive function , 2005, Nature Neuroscience.

[14]  C. Almeida,et al.  Oligomerization of Alzheimer's β-Amyloid within Processes and Synapses of Cultured Neurons and Brain , 2004, The Journal of Neuroscience.

[15]  Kang Hu,et al.  High-Level Neuronal Expression of Aβ1–42 in Wild-Type Human Amyloid Protein Precursor Transgenic Mice: Synaptotoxicity without Plaque Formation , 2000, The Journal of Neuroscience.

[16]  L. Lue,et al.  Soluble Amyloid β Peptide Concentration as a Predictor of Synaptic Change in Alzheimer’s Disease , 1999 .

[17]  J. Ting,et al.  Amyloid precursor protein overexpression depresses excitatory transmission through both presynaptic and postsynaptic mechanisms , 2007, Proceedings of the National Academy of Sciences.

[18]  L. Lannfelt,et al.  The Arctic Alzheimer mutation facilitates early intraneuronal Aβ aggregation and senile plaque formation in transgenic mice , 2006, Neurobiology of Aging.

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

[20]  M. Ohno,et al.  Intraneuronal β-Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer's Disease Mutations: Potential Factors in Amyloid Plaque Formation , 2006, The Journal of Neuroscience.

[21]  P. Davies,et al.  Hydrofluoric acid-treated tau PHF proteins display the same biochemical properties as normal tau. , 1992, The Journal of biological chemistry.

[22]  D. Mann,et al.  Deposition of beta-amyloid subtypes 40 and 42 differentiates dementia with Lewy bodies from Alzheimer disease. , 1999, Archives of neurology.

[23]  Shaomin Li,et al.  Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory , 2008, Nature Medicine.

[24]  M. Mattson,et al.  Triple-Transgenic Model of Alzheimer's Disease with Plaques and Tangles Intracellular Aβ and Synaptic Dysfunction , 2003, Neuron.

[25]  F. LaFerla,et al.  A dynamic relationship between intracellular and extracellular pools of Abeta. , 2006, The American journal of pathology.

[26]  Roger M. Nitsch,et al.  Intracellular Aβ and cognitive deficits precede β-amyloid deposition in transgenic arcAβ mice , 2007, Neurobiology of Aging.

[27]  E. Bigio,et al.  Alzheimer's disease-type neuronal tau hyperphosphorylation induced by Aβ oligomers , 2008, Neurobiology of Aging.

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

[29]  W. Klein,et al.  The E693Delta mutation in amyloid precursor protein increases intracellular accumulation of amyloid beta oligomers and causes endoplasmic reticulum stress-induced apoptosis in cultured cells. , 2009, The American journal of pathology.

[30]  Carl W. Cotman,et al.  Common Structure of Soluble Amyloid Oligomers Implies Common Mechanism of Pathogenesis , 2003, Science.

[31]  K. Akagawa,et al.  Syntaxin 5 interacts with presenilin holoproteins, but not with their N- or C-terminal fragments, and affects beta-amyloid peptide production. , 2004, The Biochemical journal.

[32]  Bernardo L Sabatini,et al.  Natural Oligomers of the Alzheimer Amyloid-β Protein Induce Reversible Synapse Loss by Modulating an NMDA-Type Glutamate Receptor-Dependent Signaling Pathway , 2007, The Journal of Neuroscience.

[33]  C. Finch,et al.  Targeting small Aβ oligomers: the solution to an Alzheimer's disease conundrum? , 2001, Trends in Neurosciences.

[34]  T. Bayer,et al.  Massive CA1/2 neuronal loss with intraneuronal and N-terminal truncated Abeta42 accumulation in a novel Alzheimer transgenic model. , 2004, The American journal of pathology.

[35]  H. Mori,et al.  Inverse correlation between amyloid precursor protein and synaptic plasticity in transgenic mice , 2007, Neuroreport.

[36]  P. Greengard,et al.  Intraneuronal Aβ42 Accumulation in Human Brain , 2000 .

[37]  Mikio Shoji,et al.  Age-Dependent Changes in Brain, CSF, and Plasma Amyloid β Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease , 2001, The Journal of Neuroscience.

[38]  L. Mucke,et al.  Accelerating Amyloid-β Fibrillization Reduces Oligomer Levels and Functional Deficits in Alzheimer Disease Mouse Models* , 2007, Journal of Biological Chemistry.

[39]  C. Duyckaerts,et al.  Alzheimer disease models and human neuropathology: similarities and differences , 2007, Acta Neuropathologica.

[40]  T. Arendt.  Neurodegeneration and plasticity , 2004, International Journal of Developmental Neuroscience.

[41]  W. K. Cullen,et al.  Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo , 2002, Nature.

[42]  J. Baron,et al.  Relationships between Hippocampal Atrophy, White Matter Disruption, and Gray Matter Hypometabolism in Alzheimer's Disease , 2008, The Journal of Neuroscience.

[43]  Yasuyoshi Watanabe,et al.  A new amyloid β variant favoring oligomerization in Alzheimer's‐type dementia , 2008, Annals of neurology.

[44]  Xin Wu,et al.  Immunization reverses memory deficits without reducing brain Aβ burden in Alzheimer's disease model , 2002, Nature Neuroscience.

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

[46]  Rie Teraoka,et al.  Amyloid-&bgr; E22Δ variant induces synaptic alteration in mouse hippocampal slices , 2008, Neuroreport.

[47]  R. Martínez-Murillo,et al.  Intra- and extracellular Abeta and PHF in clinically evaluated cases of Alzheimer's disease. , 2004, Histology and histopathology.

[48]  C. A. Wiley,et al.  A Dynamic Relationship between Intracellular and Extracellular Pools of Aβ , 2007 .

[49]  D. Ruano,et al.  Inflammatory Response in the Hippocampus of PS1M146L/APP751SL Mouse Model of Alzheimer's Disease: Age-Dependent Switch in the Microglial Phenotype from Alternative to Classic , 2008, The Journal of Neuroscience.

[50]  M. Gallagher,et al.  A specific amyloid-β protein assembly in the brain impairs memory , 2006, Nature.

[51]  R. J. Mullen,et al.  NeuN, a neuronal specific nuclear protein in vertebrates. , 1992, Development.

[52]  H. Kung,et al.  Congo red and thioflavin‐T analogs detect Aβ oligomers , 2007 .

[53]  D L Price,et al.  A vector for expressing foreign genes in the brains and hearts of transgenic mice. , 1996, Genetic analysis : biomolecular engineering.