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

  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},
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.

Effects of secreted oligomers of amyloid β‐protein on hippocampal synaptic plasticity: a potent role for trimers

The hypothesis that diffusible oligomers of Aβ initiate a synaptic dysfunction that may be an early event in AD is supported and specific assemblies, particularly timers of naturally secreted Aβ oligomers are potent and selective inhibitors of certain forms of hippocampal LTP.

Secreted Amyloid β-Proteins in a Cell Culture Model Include N-Terminally Extended Peptides That Impair Synaptic Plasticity

It is concluded that certain synaptotoxic Aβ-containing species can arise from APP processing events N-terminal to the classical β-secretase cleavage site.

Amyloid β protein immunotherapy neutralizes Aβ oligomers that disrupt synaptic plasticity in vivo

The ability of exogenous and endogenous antibodies to rapidly neutralize soluble Aβ oligomers that disrupt synaptic plasticity in vivo suggests that treatment with such antibodies might show reversible cognitive deficits in early Alzheimer disease.

Soluble oligomers of the amyloid β-protein impair synaptic plasticity and behavior

  • D. Selkoe
  • Biology
    Behavioural Brain Research
  • 2008

Certain Inhibitors of Synthetic Amyloid β-Peptide (Aβ) Fibrillogenesis Block Oligomerization of Natural Aβ and Thereby Rescue Long-Term Potentiation

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.

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

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.

Cellular Prion Protein Mediates Impairment of Synaptic Plasticity by Amyloid-β Oligomers

The cellular prion protein (PrPC) is identified as an amyloid-β-oligomer receptor by expression cloning, and PrPC-specific pharmaceuticals may have therapeutic potential for Alzheimer’s disease.

Formation of highly toxic soluble amyloid beta oligomers by the molecular chaperone prefoldin

Results suggest that Pyrococcus PFD may be involved in the formation of toxic soluble Aβ oligomers in the cytosolic compartment in’vivo.

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

It is shown that the LTP impairment induced by Aβ oligomers can be fully reversed by PP1 inhibition in vitro, and it is demonstrated that the genetic inhibition of endogenous PP1 in vivo confers resistance to A β oligomer-mediated toxicity and preserves LTP.

Enhanced neuronal degradation of amyloid-β oligomers allows synapse regeneration

  • C. Bate
  • Biology, Chemistry
    Neural regeneration research
  • 2015
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.



Use-Dependent Effects of Amyloidogenic Fragments of β-Amyloid Precursor Protein on Synaptic Plasticity in Rat Hippocampus In Vivo

It is discovered that β-amyloid peptide and the Aβ-containing C -terminus of β-APP (CT) facilitate the induction of LTD in the CA1 area of the intact rat hippocampus, which will result in a profound disruption of information processing dependent on hippocampal synaptic plasticity.

Aggregation of Secreted Amyloid -Protein into Sodium Dodecyl Sulfate-stable Oligomers in Cell Culture (*)

The ability to detect and quantitate oligomers of secreted Aβ peptides in cell culture should facilitate dynamic studies of the critical process of initial Aβ aggregation under physiological conditions.

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

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.

Protofibrillar Intermediates of Amyloid β-Protein Induce Acute Electrophysiological Changes and Progressive Neurotoxicity in Cortical Neurons

The results raise the possibility that the preclinical and early clinical progression of AD is driven in part by the accumulation of specific Aβ assembly intermediates formed during the process of fibrillogenesis, and suggest that PF have inherent biological activity similar to that of mature fibrils.

Amyloid beta-protein fibrillogenesis. Structure and biological activity of protofibrillar intermediates.

Alzheimer's disease is characterized by extensive cerebral amyloid deposition. Amyloid deposits associated with damaged neuropil and blood vessels contain abundant fibrils formed by the amyloid

Insulin-degrading Enzyme Regulates Extracellular Levels of Amyloid β-Protein by Degradation*

It is concluded that a principal protease capable of down-regulating the levels of secreted Aβ extracellularly is IDE, and activity was unexpectedly found be associated with a time-dependent oligomerization of synthetic Aβ at physiological levels in the conditioned media of cultured cells.

Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red.

  • A. LorenzoB. Yankner
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 1994
The results indicate that beta A neurotoxicity requires fibril formation, and suggest that a common cytopathic effect of amyloid fibrils may contribute to the pathogenesis of Alzheimer disease and other amyloidsoses.

Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models.

  • A. HsiaE. Masliah L. Mucke
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 1999
It is shown that overexpression of FAD(717V-->F)-mutant human APP in neurons of transgenic mice decreases the density of presynaptic terminals and neurons well before these mice develop amyloid plaques, suggesting a neurotoxic effect of Abeta that is independent of plaque formation.

Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins.

It is hypothesized that impaired synaptic plasticity and associated memory dysfunction during early stage Alzheimer's disease and severe cellular degeneration and dementia during end stage could be caused by the biphasic impact of Abeta-derived diffusible ligands acting upon particular neural signal transduction pathways.