Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature. 2002 Apr 4;416(6880):535-9. PubMed.

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  1. Our study identifies a specific form of naturally produced human amyloid beta protein, namely stable low-n oligomers, as directly interrupting a key correlate of memory and learning in a living animal. Previous research by many scientists had linked Ab in general to interruption of neural function, but precisely which form of the protein and how that occurred under natural conditions remained obscure. We now identify a specific form of naturally secreted Ab and show directly in living, anesthetized rats that it blocks long-term potentiation in the absence of monomers, protofibrils and fibrils. Thus soluble, diffusible Ab oligomers can interrupt memory circuits in the brain.

    Finally, we use a chemical compound that inhibits the production of Aβ to lower the oligomers enough to completely prevent the synaptic interruption, while still leaving appreciable monomer levels (60 percent of normal). This supports the potential utility of modest doses of β- or γ-secretase inhibitors in the disease.

    View all comments by Dennis Selkoe

  2. Previous work by the labs of Klein and Krafft showed that synthetic Aβ aggregates, termed ADDLs, are highly toxic and inhibit hippocampal function. This work now elegantly shows that Aβ oligomers generated in cells are also toxic. One puzzling aspect of this work is why such oligomers would not cause disease in familial AD patients early on in life, since they are presumably being generated continually. This suggests that although the oligomers are toxic, other factors might also contribute to the ultimate neurodegenerative toxicity - perhaps factors related to the accumulation of Aβ oligomers.

    View all comments by Benjamin Wolozin

  3. Please see the following letter published at British Medical Journal that comments on this article:

    Amyloid hypothesis, synaptic function, and Alzheimer’s disease, or: Beware: the dogma is revitalized
    Alexei R. Koudinov, Natalia V. Koudinova
    BMJ online, Published 15 May 2002 [ Full Text ].

    View all comments by Alexei Koudinov

  4. This milestone paper has addressed several issues with elegant experiments, dealing with intracellular generation of Aβ peptides and its oligomerization in cellular compartments. It is now clear that the tendency of the Aβ peptides to oligomerize and form fibrils is high. Several ideas seem striking; for example, is a particular milieu required to form these fibrils inside the cellular system? Probably the answer is “yes” but we need much more data. It has also been established that synthetic peptides have less fibrillar toxicity on synaptic plasticity when compared to Aβ generated inside cells. Now the important questions that need to be addressed from several aspects are, What is the biological significance of fibril formation and is there any process inside the cell to prevent formation of these fibrils? Scientists around the globe have been trying to understand this phenomenon and have gotten important information; this will help to understand disease pathology and its progression.

    Through the results in this article, we came to know that these Aβ peptides are present in cellular compartments, particularly in recycling endosomes. These organelles help maintain the density of receptors at various synapses; therefore, the integrity of the recycling endosomes is very important. Recently, Wang et al. reported that upon activation of NMDA receptors during LTP, the calcium sensor motor molecule Myosin Vb is recruited to recycling endosomes and is responsible for the carriage of glutamate receptors to dendritic spines, hence provides a basis for LTP and, in turn, learning and memory. In the future it will be important to see if Aβ in the recycling endosomes interferes with receptor recruitment. This can open new vistas in terms of understanding disease pathophysiology.

    References:

    Wang Z, Edwards JG, Riley N, Provance DW, Karcher R, Li XD, Davison IG, Ikebe M, Mercer JA, Kauer JA, Ehlers MD. Myosin Vb mobilizes recycling endosomes and AMPA receptors for postsynaptic plasticity. Cell. 2008 Oct 31;135(3):535-48. PubMed.

    View all comments by Touqeer Ahmed

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