Wang Z, Wang B, Yang L, Guo Q, Aithmitti N, Songyang Z, Zheng H.
Presynaptic and postsynaptic interaction of the amyloid precursor protein promotes peripheral and central synaptogenesis.
J Neurosci. 2009 Sep 2;29(35):10788-801.
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Comment on Herz et al.
This work addresses an exciting target in therapeutic approaches against Alzheimer disease: saving the synapse. Joachim Herz and colleagues recognized that some compounds promote synaptic strength, and have used this knowledge to counteract the negative effects of Aβ on the synapse. Specifically, they have found that Reelin, by signaling through the Src family kinases, prevents Aβ-induced synaptotoxicity. The research brings together an increasing understanding of the effects of Aβ (and Aβ oligomers) on synaptic deficits with growing research into the functions of Reelin on promoting synaptic strength.
There are several interesting aspects to this work. One, since it involves ApoE receptors in the mechanism of Reelin, it raises the possibility that APOE genotype affects the risk of AD at least partially through effects of ApoE on synapses. Two, it identifies non-traditional targets for AD therapeutic approaches, i.e., activation of ApoE receptors and Src family kinases, particularly for pathological processes that occur early in the disease course (loss of synapses). Three, it underscores the idea that Reelin has important functions in the adult brain, and not just during neuronal migration in development.
This research supports some very interesting avenues for research. Does Aβ affect normal functions of ApoE receptors or Src family kinases? Do ApoE isoforms have differential effects on synaptic signaling processes relevant to their risk for AD? Is targeting the molecules identified in their nice model of synaptic dysfunction in AD useful in preventing the progression of AD? It’s a rich area.
The three papers [1-3] discussed in this Research News are highly relevant for the pathogenic mechanisms of Alzheimer disease. They are tied together by their common focus on the synapse, and the way in which APP, or its proteolytic fragment, Aβ, influences synaptic function. Yet, the papers project different views on how synaptic function is perturbed in AD. Two of them [1,2] describe possible ways by which the toxic effects of Aβ on synaptic function could be alleviated. The third paper  reports on a novel function of APP in the formation of the synapse, and proposes that this function may be perturbed in AD, causing the synaptic dysfunction that is characteristic for the disease. Thus, the old question of whether AD is the result of the gain of (toxic) function inflicted by the accumulated Aβ, or of the loss of function of APP by abnormal processing, is revived. Most likely, the synaptic pathology that accompanies AD is the result of a combination of gain- and loss-of-function events leading to the disruption of a number of cellular processes downstream from cleavage and intracellular transport of APP. Sooner or later, the enormous amount of research conducted on APP will clarify these molecular and cellular dysregulations.
Unfortunately, APP undergoes a complex cell biology, and may exert its multiple functions both as full-length protein and as cleaved fragments . Thus, there are probably many functions to be lost and many toxic effects to be gained when the metabolism of APP is perturbed, as likely is the case in AD. From the researcher’s point of view, studying APP is both interesting and very challenging. Hopefully, all this exciting research will soon bring some relief to those predisposed to, or suffering from AD.
The results are very interesting and relate closely to findings we obtained in hAPP transgenic mice and humans with AD (1). In our study, we documented a depletion of reelin-positive pyramidal neurons in layer II of the entorhinal cortex in both the experimental models and the human condition. Because efferent projections of these cells could serve as a source of reelin in the hippocampus, we speculated that the depletion of reelin-producing pyramidal neurons in the entorhinal cortex might be associated with decreased reelin levels in the hippocampus, a hypothesis we were able to confirm in hAPP mice. Together with the new findings by Durakoglugil et al., these observations suggest that the Aβ-induced depletion of reelin adds insult to injury, as it would disable the very mechanism the brain could use to counteract the adverse effects of Aβ on synaptic functions.