Cellular Pathology in Alzheimer’s Disease: Implications for Corticocortical Disconnection and Differential Vulnerability

Summary

Detailed regional and laminar analyses of the neuropathological lesions in Alzheimer’s disease have led several investigators to hypothesize that key corticocortical and hippocampal circuits are compromised. In fact it has been suggested that a global corticocortical disconnection occurs in Alzheimer’s disease, thereby disrupting cohesive, integrated cortical functions and leading to dementia. Our efforts in Alzheimer’s disease research are proceeding along two related pathways. First, we are analyzing the pathological human cortex to develop a more detailed profile of the morphology and biochemical phenotype of the subset of neocortical neurons that are vulnerable top degeneration and/or neurofibrillary tangle formation. The second research strategy is to use experimental methods in a nonhuman primate to characterize the morphology, biochemical phenotype, and afferents to the pyramidal cells that furnish long corticocortical projections. Our intention is to correlate the results from the monkey experimental analyses with our neuropathological results to further characterize the degree to which the vulnerable corticocortical neurons in Alzheimer’s disease represent the human homologue of the eorticocortieally projecting neurons under study in the monkey. Within this context we have demonstrated that SMI-32, a monoclonal antibody to nonphosphorylated neurofilament protein, labels a subpopulation of pyramidal cells in layers III and V of neocortical association areas. The morphology and location of these neurons suggest that they furnish long corticocortical projections. In addition, combined immunohistochemistry transport studies in monkey demonstrated that certain corticocortically projecting neurons are SMI- 32-immunoreactive. The relative proportion of the corticocortical input to a given location that is SMI-32-immunoreactive varies systematically depending on the source of the projection, but up to 85% of the cells furnishing the projection from inferior temporal to dorsal prefrontal cortex are SMI-32-immunoreactive. Combined intracellular injection-retrograde transport studies demonstrated that, while this projection from inferior temporal cortex to dorsal prefrontal cortex may reflect a huge degree of biochemical homogeneity regarding SMI-32, the cells of origin are a morphologically diverse group. Antisera to calcium-binding proteins demonstrated that, while certain pyramidal cells might have heightened vulnerability in Alzheimer’s disease, the GABAergic interneurons labeled by antisera to calcium-binding proteins do not display any cell loss in Alzheimer’s disease. Thus, the biochemical and anatomical profiles of the vulnerable and pathology-resistant cells in Alzheimer’s disease are becoming increasingly comprehensive; however, a precise biochemical or morphological “signature” for vulnerability has not yet emerged.