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.

[1]  C. Gerday,et al.  Monoclonal antibodies directed against the calcium binding protein parvalbumin. , 1988, Cell calcium.

[2]  S. Zeki,et al.  The Organization of Connections between Areas V5 and V1 in Macaque Monkey Visual Cortex , 1989, The European journal of neuroscience.

[3]  L. Sternberger,et al.  Monoclonal antibodies distinguish phosphorylated and nonphosphorylated forms of neurofilaments in situ. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[4]  F. E. Bloom,et al.  Calbindin immunoreactivity alternates with cytochrome c-oxidase-rich zones in some layers of the primate visual cortex , 1986, Nature.

[5]  S. Zeki,et al.  The Organization of Connections between Areas V5 and V2 in Macaque Monkey Visual Cortex , 1989, The European journal of neuroscience.

[6]  N. Giard,et al.  Balint's Syndrome , 1980, Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques.

[7]  T. Crow,et al.  Location of neuronal tangles in somatostatin neurones in Alzheimer's disease , 1985, Nature.

[8]  H. Wiśniewski,et al.  Abnormal phosphorylation of the microtubule-associated protein? (tau) in Alzheimer cytoskeletal pathology , 1987 .

[9]  G. Perry,et al.  Paired helical filaments from Alzheimer disease patients contain cytoskeletal components. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[10]  Janice E. Knoefel,et al.  Clinical neurology of aging , 1985 .

[11]  H. Wiśniewski,et al.  Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[12]  D. Selkoe,et al.  Biochemistry of altered brain proteins in Alzheimer's disease. , 1989, Annual review of neuroscience.

[13]  J. Morrison,et al.  Quantitative morphology and regional and laminar distributions of senile plaques in Alzheimer's disease , 1985, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[14]  T. Voigt,et al.  Morphology of the cells within the inferior temporal gyrus that project to the prefrontal cortex in the macaque monkey , 1990, The Journal of comparative neurology.

[15]  G. V. Van Hoesen,et al.  Alzheimer's disease: Glutamate depletion in the hippocampal perforant pathway zone , 1987, Annals of neurology.

[16]  Leslie G. Ungerleider,et al.  Object vision and spatial vision: two cortical pathways , 1983, Trends in Neurosciences.

[17]  M. Fabri,et al.  Immunocytochemical evidence for glutamatergic cortico-cortical connections in monkeys , 1988, Brain Research.

[18]  D. C. Van Essen,et al.  Concurrent processing streams in monkey visual cortex , 1988, Trends in Neurosciences.

[19]  G. K. Wilcock,et al.  Plaques, tangles and dementia A quantitative study , 1982, Journal of the Neurological Sciences.

[20]  J. Penney,et al.  Alterations in L-glutamate binding in Alzheimer's and Huntington's diseases. , 1985, Science.

[21]  R. DeTeresa,et al.  Some morphometric aspects of the brain in senile dementia of the alzheimer type , 1981, Annals of neurology.

[22]  M J Campbell,et al.  Laminar and regional distributions of neurofibrillary tangles and neuritic plaques in Alzheimer's disease: a quantitative study of visual and auditory cortices , 1987, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[23]  H. Braak,et al.  Chapter 12 Ratio of pyramidal cells versus non-pyramidal cells in the human frontal isocortex and changes in ratio with ageing and Alzheimer's disease , 1986 .

[24]  J. Morrison,et al.  Selective Disconnection of Specific Visual Association Pathways in Cases of Alzheimer's Disease Presenting with Balint's Syndrome , 1990, Journal of neuropathology and experimental neurology.

[25]  M. Roth,et al.  Cortical neuronal counts in normal elderly controls and demented patients , 1983, Neurobiology of Aging.

[26]  J. Morrison,et al.  Monoclonal antibody to neurofilament protein (SMI‐32) labels a subpopulation of pyramidal neurons in the human and monkey neocortex , 1989, The Journal of comparative neurology.

[27]  D. Collerton,et al.  Cholinergic function and intellectual decline in Alzheimer's disease , 1986, Neuroscience.

[28]  M. Rossor Neurotransmitters and CNS disease. Dementia. , 1982, Lancet.

[29]  J. Morrison,et al.  Balit's syndrome in Alzheimer's disease: specific disruption of the occipito-parietal visual pathway , 1989, Brain Research.

[30]  R. DeTeresa,et al.  Neocortical morphometry, lesion counts, and choline acetyltransferase levels in the age spectrum of Alzheimer's disease , 1988, Neurology.

[31]  B. Katz,et al.  Ophthalmologic manifestations of Alzheimer's disease. , 1989, Survey of ophthalmology.

[32]  G. V. Van Hoesen,et al.  Perforant pathway changes and the memory impairment of Alzheimer's disease , 1986, Annals of neurology.

[33]  D. Selkoe,et al.  Tau Epitopes are Incorporated into a Range of Lesions in Alzheimer's Disease , 1987, Journal of neuropathology and experimental neurology.

[34]  L. Otvos,et al.  Identification of the major multiphosphorylation site in mammalian neurofilaments. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[35]  F. E. Bloom,et al.  Loss of pigmented dopamine-β-hydroxylase positive cells from locus coeruleus in senile dementia of alzheimer's type , 1983, Neuroscience Letters.

[36]  G K Wilcock,et al.  Anatomical correlates of the distribution of the pathological changes in the neocortex in Alzheimer disease. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[37]  John H. Morrison,et al.  A monoclonal antibody to non-phosphorylated neurofilament protein marks the vulnerable cortical neurons in Alzheimer's disease , 1987, Brain Research.

[38]  H. Barbas Pattern in the laminar origin of corticocortical connections , 1986, The Journal of comparative neurology.

[39]  L. Iversen,et al.  Neurochemical characteristics of early and late onset types of Alzheimer's disease. , 1984, British medical journal.