Impaired spine stability underlies plaque-related spine loss in an Alzheimer's disease mouse model.

Dendritic spines, the site of most excitatory synapses in the brain, are lost in Alzheimer's disease and in related mouse models, undoubtedly contributing to cognitive dysfunction. We hypothesized that spine loss results from plaque-associated alterations of spine stability, causing an imbalance in spine formation and elimination. To investigate effects of plaques on spine stability in vivo, we observed cortical neurons using multiphoton microscopy in a mouse model of amyloid pathology before and after extensive plaque deposition. We also observed age-matched nontransgenic mice to study normal effects of aging on spine plasticity. We found that spine density and structural plasticity are maintained during normal aging. Tg2576 mice had normal spine density and plasticity before plaques appeared, but after amyloid pathology is established, severe disruptions were observed. In control animals, spine formation and elimination were equivalent over 1 hour of observation ( approximately 5% of observed spines), resulting in stable spine density. However, in aged Tg2576 mice spine elimination increased, specifically in the immediate vicinity of plaques. Spine formation was unchanged, resulting in spine loss. These data show a small population of rapidly changing spines in adult and even elderly mouse cortex; further, in the vicinity of amyloid plaques, spine stability is markedly impaired leading to loss of synaptic structural integrity.

[1]  H. B. M. Uylings,et al.  Morphometric and dendritic analysis of fascia dentata granule cells in human aging and senile dementia , 1987, Brain Research.

[2]  D. Mann,et al.  A quantitative morphometric analysis of the neuronal and synaptic content of the frontal and temporal cortex in patients with Alzheimer's disease , 1987, Journal of the Neurological Sciences.

[3]  I. Ferrer,et al.  Decreased numbers of dendritic spines on cortical pyramidal neurons in dementia. A quantitative Golgi study on biopsy samples. , 1988, Human neurobiology.

[4]  D. Salmon,et al.  Physical basis of cognitive alterations in alzheimer's disease: Synapse loss is the major correlate of cognitive impairment , 1991, Annals of neurology.

[5]  E. Masliah,et al.  Synaptic and neuritic alterations during the progression of Alzheimer's disease , 1994, Neuroscience Letters.

[6]  S. DeKosky,et al.  Structural correlates of cognition in dementia: quantification and assessment of synapse change. , 1996, Neurodegeneration : a journal for neurodegenerative disorders, neuroprotection, and neuroregeneration.

[7]  B. Hyman,et al.  Abeta associated neuropil changes: correlation with neuronal loss and dementia. , 1998, Journal of neuropathology and experimental neurology.

[8]  M. Hasselmo,et al.  Plaque-induced neurite abnormalities: implications for disruption of neural networks in Alzheimer's disease. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[9]  Kristen M Harris,et al.  Structure, development, and plasticity of dendritic spines , 1999, Current Opinion in Neurobiology.

[10]  A. Fagan,et al.  Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[11]  K. Svoboda,et al.  Experience-dependent plasticity of dendritic spines in the developing rat barrel cortex in vivo , 2000, Nature.

[12]  R. Yuste,et al.  Regulation of Spine Calcium Dynamics by Rapid Spine Motility Materials and Methods , 2022 .

[13]  A. Matus,et al.  Actin-based plasticity in dendritic spines. , 2000, Science.

[14]  D. Selkoe,et al.  Toward a Comprehensive Theory for Alzheimer's Disease. Hypothesis: Alzheimer's Disease Is Caused by the Cerebral Accumulation and Cytotoxicity of Amyloid β‐Protein , 2000, Annals of the New York Academy of Sciences.

[15]  J. Vickers,et al.  The morphological phenotype of β-amyloid plaques and associated neuritic changes in Alzheimer’s disease , 2001, Neuroscience.

[16]  K. Svoboda,et al.  Rapid Development and Plasticity of Layer 2/3 Maps in Rat Barrel Cortex In Vivo , 2001, Neuron.

[17]  B. Hyman,et al.  Imaging Aβ Plaques in Living Transgenic Mice with Multiphoton Microscopy and Methoxy‐X04, a Systemically Administered Congo Red Derivative , 2002, Journal of neuropathology and experimental neurology.

[18]  Kristen M Harris,et al.  Dendritic Spine Pathology: Cause or Consequence of Neurological Disorders? , 2002, Brain Research Reviews.

[19]  K. Svoboda,et al.  Long-term in vivo imaging of experience-dependent synaptic plasticity in adult cortex , 2002, Nature.

[20]  B. Hyman,et al.  Non-Fc-Mediated Mechanisms Are Involved in Clearance of Amyloid-β In Vivo by Immunotherapy , 2002, The Journal of Neuroscience.

[21]  T. Lanz,et al.  Dendritic spine loss in the hippocampus of young PDAPP and Tg2576 mice and its prevention by the ApoE2 genotype , 2003, Neurobiology of Disease.

[22]  P. Coleman,et al.  Synaptic slaughter in Alzheimer’s disease , 2003, Neurobiology of Aging.

[23]  Gregory A. Hickey,et al.  Amyloid-β Antibody Treatment Leads to Rapid Normalization of Plaque-Induced Neuritic Alterations , 2003, The Journal of Neuroscience.

[24]  B. Hyman,et al.  In Vivo Multiphoton Imaging of a Transgenic Mouse Model of Alzheimer Disease Reveals Marked Thioflavine‐S‐Associated Alterations in Neurite Trajectories , 2003, Journal of neuropathology and experimental neurology.

[25]  Mriganka Sur,et al.  Motility of dendritic spines in visual cortex in vivo: Changes during the critical period and effects of visual deprivation , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[26]  Brian J Bacskai,et al.  In Vivo Imaging of Reactive Oxygen Species Specifically Associated with Thioflavine S-Positive Amyloid Plaques by Multiphoton Microscopy , 2003, The Journal of Neuroscience.

[27]  J. Wegiel,et al.  Contribution of glial cells to the development of amyloid plaques in Alzheimer’s disease , 2004, Neurobiology of Aging.

[28]  C. Finch,et al.  Synaptic Targeting by Alzheimer's-Related Amyloid β Oligomers , 2004, The Journal of Neuroscience.

[29]  O. Vitolo,et al.  Dendrite and dendritic spine alterations in alzheimer models , 2004, Journal of neurocytology.

[30]  Edward A. Stern,et al.  Cortical Synaptic Integration In Vivo Is Disrupted by Amyloid-β Plaques , 2004, The Journal of Neuroscience.

[31]  Jaime Grutzendler,et al.  Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal branches , 2004, Nature Neuroscience.

[32]  T. Spires,et al.  Neuronal Structure is Altered by Amyloid Plaques , 2004, Reviews in the neurosciences.

[33]  H. Braak,et al.  Neuropathological stageing of Alzheimer-related changes , 2004, Acta Neuropathologica.

[34]  W. Gan,et al.  Development of Long-Term Dendritic Spine Stability in Diverse Regions of Cerebral Cortex , 2005, Neuron.

[35]  A. Matus.  Growth of dendritic spines: a continuing story , 2005, Current Opinion in Neurobiology.

[36]  Einar M. Sigurdsson,et al.  Amyloid proteins : methods and protocols , 2005 .

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

[38]  E. Masliah,et al.  β-Amyloid Immunotherapy Prevents Synaptic Degeneration in a Mouse Model of Alzheimer's Disease , 2005, The Journal of Neuroscience.

[39]  G. Shepherd,et al.  Transient and Persistent Dendritic Spines in the Neocortex In Vivo , 2005, Neuron.

[40]  Brian J. Bacskai,et al.  In Vivo Imaging of Amyloid-ß Deposits in Mouse Brain With Multiphoton Microscopy , 2005 .

[41]  P. Greengard,et al.  Beta-amyloid accumulation in APP mutant neurons reduces PSD-95 and GluR1 in synapses , 2005, Neurobiology of Disease.

[42]  P. Livrea,et al.  Soluble β-Amyloid1-40 Induces NMDA-Dependent Degradation of Postsynaptic Density-95 at Glutamatergic Synapses , 2005, The Journal of Neuroscience.

[43]  P. T. Nguyen,et al.  Dendritic Spine Abnormalities in Amyloid Precursor Protein Transgenic Mice Demonstrated by Gene Transfer and Intravital Multiphoton Microscopy , 2005, The Journal of Neuroscience.

[44]  C. Blakemore,et al.  Activity-dependent Regulation of Synapse and Dendritic Spine Morphology in Developing Barrel Cortex Requires Phospholipase C-β1 Signalling , 2005 .

[45]  P. Greengard,et al.  Regulation of NMDA receptor trafficking by amyloid-β , 2005, Nature Neuroscience.

[46]  C. Dotti,et al.  Localized recruitment and activation of RhoA underlies dendritic spine morphology in a glutamate receptor–dependent manner , 2006, The Journal of cell biology.

[47]  K. Ashe,et al.  Commentary on “Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice” , 2006 .

[48]  S. Strittmatter,et al.  Alzheimer Precursor Protein Interaction with the Nogo-66 Receptor Reduces Amyloid-β Plaque Deposition , 2006, The Journal of Neuroscience.

[49]  Mark Bowlby,et al.  Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer's disease. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[50]  C. Barnes,et al.  Neural plasticity in the ageing brain , 2006, Nature Reviews Neuroscience.

[51]  W. Gan,et al.  Choice of cranial window type for in vivo imaging affects dendritic spine turnover in the cortex , 2007, Nature Neuroscience.

[52]  C. Dotti,et al.  Transmitting on actin: synaptic control of dendritic architecture , 2007, Journal of Cell Science.

[53]  A. Nappi,et al.  Alzheimer ' s Disease : Cell-Specific Pathology Isolates the Hippocampal Formation , 2022 .