A Model of Apoptosis in Neocortex

Neurons in the cerebral cortex communicate with each other via connections termed ” the associative pathways” because they allow various types of information processed at the cortical level (sensory from the skin, visceral, proprioceptive) to be combined in a “multimodal” way and to create more complex representations of the environment in the animal’s brain. These pathways, and the neurons that participate in them (associative neurons), are vulnerable in AD. In tum, the degeneration of these associative systems deprive patients with AD of the most important faculties of the mind (i.e., the ability to make sense of the world CgnosiaJ, to remember (memory), and to execute complex acts (praxis)). Of particular importance is the degeneration of neurons in the entorhinal area (i.e., a part of cortex that combines information from a variety of sensory cortical areas and relays it to the hippocampus, so that memories are formed and solidified in an appropriate context). The mechanisms of this selective vulnerability of cortico-cortical connections, with their major impact in areas such as the entorhinal cortex, are not understood. Although several genes have been identified that cause or contribute to AD, the molecular information that follows these discoveries needs to be coupled with mechanisms that operate at the level of brain systems. This combination will allow a stepwise understanding of the pathogenesis of the disease and, more importantly, facilitate the design of rational and effective treatments.

We propose a relatively simple experimental approach that would allow a better understanding of the corticocortical degeneration that occurs in AD and, at the same time, would provide a model for testing drugs to prevent or ameliorate cortical degeneration. Our approach is founded in our recent discovery that pyramidal neurons in the olfactory cortex undergo programmed cell death (“apoptosis”) after we interrupt their inputs from the olfactory bulb (bulbectomy). Because the olfactory bulb is a primitive, two-layer cortex, the bulb-to-piriform cortex connection is a simple example of a cortico-cortical system. This finding is very interesting for three reasons. First, it is the first time that we have a reliable mode l of death of cortical neurons in vivo. Second, the type of death these cells undergo after bulbectomy (apoptosis) is an active process (resembling a cell suicide) and is considered as a “generic” process via which neurons degenerate and die in a variety of diseases as well as during development. As such, apoptosis has attracted unparalleled interest, and there is already a lot of information on the involved genes and molecular mechanisms, mostly from work in vitro. Third, apoptosis in olfactory cortical neurons after bulbectomy proceeds relatively quickly (i.e., takes be completed, a time window that is almost ideal for a practical investigation of detailed mechanisms involved in this process). More recently, we have extended the bulbectomy model to study the degeneration of entorhinal cortical associative neurons (i.e., neurons like those that degenerate in AD). As above, these entorhinal cells are associative neurons and receive input from many distinct cortical areas (they are “multimodal” neurons). Therefore, to deprive them of their cortical inputs, we must destroy more than one cortical area. Based on very recent work in our laboratory, this is a feasible experiment that, very importantly, has the same effects on entorhinal neurons as bulbectomy has for olfactory neurons – it leads to cell death within a short period of time. The extension of the bulbectomy model to the entorhinal disconnection model takes us much closer to what is actually happening in AD and provides a way of bridging an experimental model with a human disease.

An additional discovery of ours is that, although olfactory cortical neurons commit apoptosis after being deprived of appropriate sensory inputs, early changes in their processes (dendrites) resemble lesions akin to the those seen in models of stroke. These lesions are mediated via the neurotransmitter glutamate (they are the result of an excess of glutamate), and several compounds are known to block them, many of which are being used or are in clinical trials for a variety of neurological diseases. If these glutamate-mediated lesions are necessary steps for the execution of apoptosis, then it is possible that the therapeutic compound we mentioned above can be used to treat cortico-cortical degeneration, regardless of the initial (largely unknown) pathogenetic events in AD. In that sense, our animal model of corticocortical degeneration will not only allow for a better understanding of the mechanisms of cortical degeneration in AD but will also provide an expedient model for testing drugs that are safe and can be given by mouth in simple regimens.