Beta amyloid and excitatory synapses

Abstract

In this short review we will focus on the effect of APP and Aβ on excitatory synaptic function, as there is considerable evidence that synapses are a key target site of Alzheimer's Disease (Terry, Masliah et al. 1991). Two aspects of synaptic function affected by Aβ can be considered: 'basal' synaptic transmission and synaptic plasticity. Of course, if synaptic plasticity is altered, and if one believes that the plasticity examined in experimental conditions occurs normally in the animal, one would expect 'basal' transmission also to be altered. It is surprising how little this concept is considered in studies that examine the effect of any genetic perturbation on synaptic plasticity. The effect of Aβ on synaptic transmission and plasticity can be examined using several experimental protocols, and it is not clear if results from different protocols should be directly compared. Nevertheless, here we will consider results from such different protocols. Essentially there are three methods one can use to determine the effect of Aβ on synaptic function: 1) direct application of synthesized or purified Aβ on neural tissue; 2) examination of transgenic animals which over-express mutant forms of APP that generate increased amounts of Aβ; or 3) transient over-expression of APP in neurons which drives increased amounts of Aβ. Each method has advantages and disadvantages. With the first method, the advantage is that the identity (namely Aβ) and concentration of active compound is known. However, the oligemerizaton state of Aβ must be carefully controlled. Furthermore, with injection of Aβ into the brain it is difficult to control the concentration of Aβ relative to the synapses being examined. With the second method, using transgenic mice, concentrations of Aβ produced can be fairly well determined and of course the effects on behavior can be assessed. However, APP is chronically over-expressed and thus there may be compensatory mechanisms that obscure determining the direct effects of Aβ on synaptic function. Furthermore, different genetic strains may produce different amounts of Aβ, and in different genetic backgrounds, which may complicate interpretations of results. With the third method, transient overexpression, the effects of various mutant forms of APP or Aβ can be compared, and the effects are relatively acute. However, levels of Aβ reaching synapses may not be easy to assess. © 2007 Springer Science+Business Media, LLC. All rights reserved.