Characterization of neuronal dystrophy induced by fibrillar amyloid beta: implications for Alzheimer's disease.
Amyloid deposition, neuronal dystrophy and synaptic loss are characteristic pathological features of Alzheimer's disease (AD). We have used cortical neuronal cultures to assess the dystrophic effect of fibrillar amyloid beta (Abeta) and its relationship with neurotoxicity and synaptic loss. Treatment with fibrillar Abeta led to the development of neuritic dystrophy in the majority of the neurons present in the culture. Morphometric analysis and viability assays showed that neuronal dystrophy appeared significantly earlier and at lower Abeta concentrations than neurotoxicity, suggesting that both effects are generated independently by different cellular mechanisms. The development of dystrophic features required Abeta fibril formation and did not depend on the presence of the RHDS adhesive domain in the sequence of Abeta. Finally, a dramatic reduction in the density of synaptophysin immunoreactivity was closely associated with dystrophic changes in viable neurons. These results suggest that aberrant plastic changes and loss of synaptic integrity induced by fibrillar Abeta may play a significant role in the development of AD pathology.
Grace
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EA
Department of Neuroscience, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA.
Rabiner
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CA
Busciglio
J
J
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D005333:Fetus; D007150:Immunohistochemistry; D009410:Nerve Degeneration / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016501:Neurites / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009454:Neurofibrils / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017434:Protein Structure, Tertiary / Q000187:drug effects / Q000502:physiology; D051381:Rats; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016708:Synaptophysin / Q000187:drug effects / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016708:Synaptophysin