Cellular Pathology in Alzheimer’s Disease: Implications for Corticocortical Disconnection and Differential Vulnerability
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.
KeywordsDementia Neurol Choline Pyramid Lawson
Unable to display preview. Download preview PDF.
- Braak H, Braak E (1986) Ratio of pyramidal cells versus non-pyramidal cells in the human frontal isocortex and changes in ratio with ageing and Alzheimer’s disease. In: Swaab DF, Fliers E, Mirmiran M, Van Gool WA, Van Haaren F (eds) Progress in Brain Research, vol 70. Elsevier, Amsterdam, pp 185–212Google Scholar
- Campbell MJ, Hof PR, Cox K, Timber TA, Young WG, Morrison JH (1989) A subset of primate corticocortical neurons are neurofilament protein (NFP) immunoreactive (ir): a combined retrograde immunohistochemical study. Proc Soc Neurosci 15:72Google Scholar
- De Lima AD, Voigt T, Morrison JH (1989) Morphology of the cells within the inferior temporal gyrus that project to the prefrontal cortex in the macaque monkey. J Comp Neurol, in pressGoogle Scholar
- Hendry SHC, Jones EG, Emson PC, Lawson DEM, Heizmann CW, Streit P (1989) Two classes of cortical GAB A neurons defined by differential calcium binding protein immunoreactivities. Exp Brain Res 767:467–472Google Scholar
- Hof PR, Cox K, Morrison JH (1988) Quantitative analysis of non-phosphorylated neurofilament protein (NPNFP)-immunoreactive neurons in normal and Alzheimer’s, disease brain. Proc Soc Neurosci 14:1086Google Scholar
- Hof PR, Bouras C, Constantinidis J, Morrison JH (1989) Selective disconnection of specific visual association pathways in cases of Alzheimer’s disease presenting with Balint’s syndrome. J Neuropathol Exp Neurol, in pressGoogle Scholar
- Kemper TL (1984) Neuroanatomical and neuropathological changes in normal aging and dementia. In: Albert ML (ed) Clinical neurology of aging. Oxford University Press, New York, pp 9–52Google Scholar
- Mishkin M, Ungerleider LG, Macko KA (1983) Object vision and spatial vision: two cortical pathways. TINS 6:414–417Google Scholar
- Morrison JH, Scherr S, Lewis DA, Campbell MJ, Bloom FE, Rogers J, Benoit R (1986) The laminar and regional distribution of neocortical somatostatin and neuritic plaques: implications for Alzheimer’s disease as a global neocortical disconnection syndrome. In: Scheibel AB, Wechsler AF (eds) The biological substrates of Alzheimer’s disease, UCLA Forum in Medical Sciences, vol 27. Academic, Orlando, pp 115–131Google Scholar
- Morrison JH, Cox K, Hof PR, Celio MR (1988) Neocortical parvalbumin-containing neurons are resistant to degeneration in Alzheimer’s disease. Proc Soc Neurosci 14:1085Google Scholar
- Rapoport SI (1987) Alzheimer’s disease: phylogenetic vulnerability of associative neocortex and its connections. In: Davies P, Finch CE (eds) Molecular neuropathology of aging, Banbury Report, vol 27. Cold Spring Harbor Laboratory, New York, pp 37–54Google Scholar
- Van Essen DC (1985) Functional organization of primate visual cortex. In: Peters A, Jones EG (eds) Cerebral cortex, vol 3 (Visual cortex). Plenum Press, New York, pp 259–329Google Scholar