Cells - a-beta inhibits long-term potentiation

Professor Dennis Selkoe notes amyloid beta oligomers are very potent inhibitors of long-term potentiation (LTP) and can 'short circuit' synapses in the hippocampus.

When we study the effects of a-beta [amyloid beta] oligomers, and we’ve isolated them from human brains from people with Alzheimer’s disease, we can put them onto a brain section of hippocampus from a mouse or a rat, or we can inject them into the brain of a mouse or a rat, and we’ve done both. We can show that they short circuit the hippocampal synapses by interfering with a phenomenon [known as] long-term potentiation or LTP. A-beta oligomers are very potent inhibitors of LTP, and we’ve learned and published recently that they are remarkably potent, that the amount of a-beta oligomers, if you harvest it from a patient who died with Alzheimer’s disease, even if there is a lot of a-beta there, the amount that you need to just interfere with LTP is not a lot, what we call sub-nanomolar quantities. 1x10-9 moles of a-beta, which would be a very small amount, would be more than sufficient to block LTP. Now, LTP is an important correlate of memory and learning, and so we think it’s meaningful that we can take a-beta out of the patient’s brain, study it biochemically, learn that its doublets and triplets and quadruplets floated onto a section of mouse hippocampus and interfere with LTP. In fact, beyond that we can actually induce what’s called LTD, as in depression, long-term synaptic depression. Oligomers will induce that, which is bad, and they’ll inhibit long-term potentiation, which is generally viewed as good. Very importantly, we can link those phenomena of LTP and LTD to memory by taking another aliquot or another little helping of the same a-beta we isolated and putting it into an awake adult rat and showing that the rat is forgetful. So, in some ways, there’s been a debate about whether LTP is unequivocally a reflection of memory symptoms and memory function in humans. We can say that, from our work on Alzheimer’s [disease], there is an excellent correlation. What happens in the Alzheimer’s [disease] patient’s brain that makes them forgetful inhibits LTP in a simpler system and makes a rat forgetful, as well. So we can connect Alzheimer’s [disease] memory loss, a rat’s memory failure with the material from an Alzheimer’s [disease] patient, and inhibition of LTP.