Determinants of Cellular Vulnerability in Alzheimer's

Both structurally and functionally, Alzheimer’s disease (AD) is predominantly a disease of the cerebral cortex. However, it is not a generalized loss of cortical function; certain cells, circuits, regions, and functions are devastated whereas others are spared. In regard to AD we must bear in mind that dementia and memory loss are the devastating consequences of the disease process that must be treated or prevented, therefore neurobiological investigations should be designed with these behavioral manifestations in mind. Just as specific circuits underlie vision or motor performance, specific circuits underlie cognition and memory, and dementia is a manifestation of the loss of these circuits. These circuits involve specific sets of neurons that are likely to possess a very high degree of morphologic and biochemical specialization, given that they are responsible for functions that are uniquely well-developed in humans. In turn, the expression of the unique biochemical and morphologic characteristics of these neurons will be dependent on molecular events and genetic regulation that will be linked to both their functional role and their heightened vulnerability in AD. Thus, the experimental analysis should be directed at identifying the crucial cells and circuits that degenerate in AD, and then developing a detailed profile of the morphologic, biochemical, and molecular genetic attributes that are specific to these neurons. At each level, the studies should be guided by existing data that point to a given circuit or molecule that has been shown to be crucial to the pathogenesis of AD.

Based on careful analyses of the distribution of pathologic profiles and cell loss in AD, we believe that the degeneration of corticocortical circuits is one of the most devastating consequences of neuronal degeneration in AD. Corticocortical circuits are the projections that interconnect functionally linked areas of cerebral cortex. In fact, we have suggested that a global corticocortical disconnection occurs in AD, in which cohesive, integrated neocortical and hippocampal functions are disrupted, resulting in dementia. In the primate brain, there is an exceedingly high degree of functional specialization in the cortex, and the cortical regions that are dedicated to a given function are heavily interconnected. For example, in the monkey, and presumably human cortex, there are at least twenty identifiable, separate cortical areas dedicated to visual processing. A given area is dedicated to motion detection, color, form, or spatial analysis, and a cohesive view of the visual world results from the communication between these various regions that are each responsible for a portion of what we consider vision. This communication across regions is the province of the corticocortical connections. Just as vision is subserved by specific sets of corticocortical circuits, so are functions such as cognition. Although the circuitry that underlies cognition is not as well-characterized as that for vision, it clearly involves the interconnections between association areas within the prefrontal, temporal and parietal areas, connections that we believe are devastated in AD.

The heightened vulnerability of the pyramidal cells of origin of the corticocortical projections in AD may be related to the anatomic and/or biochemical profile of these highly specialized neurons. We have hypothesized that cortical pyramidal cells in general, and those furnishing corticocortical projections in particular, can be differentiated and categorized based on their location, biochemical characteristics, connectivity, and structural characteristics. We have further hypothesized the following: 1) Certain structural proteins that have been implicated in the pathogenesis of AD will be a crucial element in the “cell-typing” of these pyramidal cells; and 2) The comprehensive profile of a given corticocortically projecting neuron, and in turn, a given corticocortical projection, will be strongly related to its role in normal cortical function and to its vulnerability in AD or other neurodegenerative disorders. In other words, we would predict that the neurons interconnecting frontal and temporal areas that are vulnerable in AD will have a different structural and biochemical profile than certain corticocortical projections in the occipital cortex (i.e. visual cortex) that are resistant to pathology in AD.

In order to develop a more comprehensive profile of these neurons, their connectivity patterns must be correlated with their location, morphology, and biochemical phenotype. We will derive these correlations through an experimental analysis of the cellular characteristics of corticocortically projecting neurons in the nonhuman primate cortex. The results from the monkey experimental analyses will be correlated with our human neuropathologic results in order to further characterize the degree to which the vulnerable cortical neurons in AD represent the human homologue of the corticocortically projecting neurons under study in monkey. It is our hope that the monkey-human comparison will lead to a cell biological and biochemical “signature” of these neurons that integrates information on connectivity from monkey with disease vulnerability in human. In all cases the analyses will have both biochemical and anatomic focus. The biochemical focus will be on several groups of cytoskeletal proteins strongly implicated in AD pathogenesis. The anatomic focus will include a diverse set of temporo-frontal-parietal corticocortical connections that are both functionally linked to cognition and highly vulnerable in AD, as well as connections subserving vision that are relatively resistant to degeneration in AD. If we can pinpoint the elements of the biochemical and anatomic phenotype that are most clearly linked to differential cellular vulnerability in AD, then we will be one step closer to developing means of protecting those neurons that degenerate in AD.

The studies outlined in this proposal represent only the initial stages of the comprehensive characterization of corticocortically projecting neurons. Studies in later years will extend the analysis to the neurotransmitters utilized by these neurons and those that modulate the activity of these neurons, the receptor profile of these neurons, and the degree to which specific growth factors impact on the differentiation and sustained health of this important class of cortical neurons. In addition, this analysis will be extended to hippocampal circuits, particularly those known to be devastated in AD.