protein in a very small, discrete region, such as a single synapse (see Figure A-1). Such an approach allows for a very high-resolution analysis of the molecular constituents of identified synapses and presumably will be able to reveal shifts in the molecular constituents with experimental manipulations and/or aging at a quantitative level. When such studies are done in behaviorally characterized aged animals, we will be able to draw direct correlations between the distribution of key synaptic molecules and age-related behavioral impairment. No such studies have been completed to date, but they are now under way.
As is apparent from the above discussion, key studies of aging have been and will continue to be directed at questions requiring different levels of resolution in the analysis. The illustrations cited below will focus on the microscopic delineation of vulnerable circuits and cell classes, as well as changes in protein distribution in specific cell classes, circuits, and neuronal compartments. While these examples will hopefully highlight the power of a circuit-based approach, they will also illuminate the present shortcomings of the data, such as a paucity of chemically specific synaptic data and the need for more interdisciplinary analyses. Electrophysiological data will be crucial in the interdisciplinary context, since they are particularly powerful at revealing the emergent properties and information content of hippocampal circuits coding for memory (Barnes et al., 1997a, 1997b; Eichenbaum et al., 1999; Shapiro and Eichenbaum, 1999; Wood et al., 1999). As the data emerge, it will be crucial to develop a set of models and/or databases that link data across studies, such that the synaptic and cellular data will be in a context that is easily linked to the functional role of a known circuit, in a region that is clearly implicated in a function that is compromised in aging, such as memory.
At the outset, it is important to draw a distinction between the neurobiological events underlying the dementia of Alzheimer's disease and those that underlie age-related memory impairment (Morrison and Hof, 1997). In Alzheimer's disease and neurodegenerative disorders in general, neuron death occurs that results in circuit disruption and profound impairment of the neural functions dependent on the degenerating circuits (see Hof et al., 1999, for a review). As mentioned above, neuron death is not ubiquitous in neurodegenerative disorders, in that neurons display a particular pattern of selective vulnerability in each disorder. In Alzheimer's disease, the highly vulnerable circuits are: (1) neurons that interconnect functionally linked neocortical areas (Pearson et al., 1985; Rogers and Morrison, 1985; Lewis et al., 1987); (2) the projection from the entorhinal cortex to the hippocampus, referred to