Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory

@article{Shankar2008AmyloidPD,
  title={Amyloid-$\beta$ protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory},
  author={Ganesh M. Shankar and Shaomin Li and Tapan Mehta and Amaya Garc{\'i}a-Mu{\~n}oz and Nina E. Shepardson and Imelda M. Smith and Francesca Brett and Michael A. Farrell and Michael J. Rowan and Cynthia A. Lemere and Ciaran M. Regan and Dominic M. Walsh and Bernardo L. Sabatini and Dennis J. Selkoe},
  journal={Nature Medicine},
  year={2008},
  volume={14},
  pages={837-842}
}
Alzheimer's disease constitutes a rising threat to public health. Despite extensive research in cellular and animal models, identifying the pathogenic agent present in the human brain and showing that it confers key features of Alzheimer's disease has not been achieved. We extracted soluble amyloid-β protein (Aβ) oligomers directly from the cerebral cortex of subjects with Alzheimer's disease. The oligomers potently inhibited long-term potentiation (LTP), enhanced long-term depression (LTD) and… 

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References

SHOWING 1-10 OF 40 REFERENCES

Natural oligomers of the amyloid-β protein specifically disrupt cognitive function

TLDR
The biochemical isolation of discrete amyloid-β moieties with pathophysiological properties sets the stage for a new approach to studying the molecular mechanisms of cognitive impairment in Alzheimer disease and related neurodegenerative disorders.

Amyloid β Protein Dimer-Containing Human CSF Disrupts Synaptic Plasticity: Prevention by Systemic Passive Immunization

TLDR
It is reported that untreated ex vivo human CSF that contains Aβ dimers rapidly inhibits hippocampal long-term potentiation in vivo and that acute systemic infusion of an anti-Aβ monoclonal antibody can prevent this disruption of synaptic plasticity.

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

TLDR
It is reported that natural oligomers of human Aβ are formed soon after generation of the peptide within specific intracellular vesicles and are subsequently secreted from the cell, indicating that synaptotoxic Aβ oligomers can be targeted therapeutically.

A specific amyloid-β protein assembly in the brain impairs memory

TLDR
It is found that memory deficits in middle-aged Tg2576 mice are caused by the extracellular accumulation of a 56-kDa soluble amyloid-β assembly, which is proposed to be Aβ*56 (Aβ star 56), which may contribute to cognitive deficits associated with Alzheimer's disease.

Natural Oligomers of the Alzheimer Amyloid-β Protein Induce Reversible Synapse Loss by Modulating an NMDA-Type Glutamate Receptor-Dependent Signaling Pathway

TLDR
It is concluded that soluble, low-n oligomers of human Aβ trigger synapse loss that can be reversed by therapeutic agents and provides a quantitative cellular model for elucidating the molecular basis of Aβ-induced neuronal dysfunction.

A specific amyloid-beta protein assembly in the brain impairs memory.

TLDR
It is found that memory deficits in middle-aged Tg2576 mice are caused by the extracellular accumulation of a 56-kDa soluble amyloid-beta assembly, which is proposed to be Abeta*56 (Abeta star 56), which may contribute to cognitive deficits associated with Alzheimer's disease.

The oligomerization of amyloid beta-protein begins intracellularly in cells derived from human brain.

TLDR
It is concluded that the pathogenically critical process of Abeta oligomers, principally dimers, in primary human neurons and in neuronal and nonneural cell lines begins intraneuronally.

Soluble Amyloid b Peptide Concentration as a Predictor of Synaptic Change in Alzheimer’s Disease

TLDR
Investigation revealed that A b 40, whether in soluble or insoluble form, was a particularly useful measure for classifying ND, HPC, and AD patients compared with A b 42, and concentrations of soluble A b clearly distinguished HPC from AD patients and were a strong inverse correlate of synapse loss.

Aβ Oligomer-Induced Aberrations in Synapse Composition, Shape, and Density Provide a Molecular Basis for Loss of Connectivity in Alzheimer's Disease

TLDR
The observed disruption of dendritic spines links ADDLs to a major facet of AD pathology, providing strong evidence that AD DLs in AD brain cause neuropil damage believed to underlie dementia.