Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo

@article{Walsh2002NaturallySO,
  title={Naturally secreted oligomers of amyloid $\beta$ protein potently inhibit hippocampal long-term potentiation in vivo},
  author={Dominic M. Walsh and Igor Klyubin and Julia V. Fadeeva and William K. Cullen and Roger Anwyl and Michael S. Wolfe and Michael J. Rowan and Dennis J. Selkoe},
  journal={Nature},
  year={2002},
  volume={416},
  pages={535-539}
}
Although extensive data support a central pathogenic role for amyloid β protein (Aβ) in Alzheimer's disease, the amyloid hypothesis remains controversial, in part because a specific neurotoxic species of Aβ and the nature of its effects on synaptic function have not been defined in vivo. [] Key Result Cerebral microinjection of cell medium containing these oligomers and abundant Aβ monomers but no amyloid fibrils markedly inhibited hippocampal long-term potentiation (LTP) in rats in vivo.

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The identification of small molecules that inhibit early Aβ oligomer formation and rescue LTP inhibition offers a rational approach for therapeutic intervention in Alzheimer's disease and highlights the utility of the cell-culture paradigm as a useful secondary screen for compounds designed to inhibit early steps in A β oligomerization under biologically relevant conditions.

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Aβ Oligomer-Mediated Long-Term Potentiation Impairment Involves Protein Phosphatase 1-Dependent Mechanisms

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The hypothesis that the slow clearance of A β from neurons is a significant factor in the accumulation of Aβ within the brain that leads to synapse damage and dementia in AD is explored.
...

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