Morphologic and Neurochemical Characteristics of Corticocortical Projections: Emergence of Circuit-specific Features and Relationships to Degenerative Changes in Alzheimer’s Disease

Conference paper
Part of the Research and Perspectives in Alzheimer’s Disease book series (ALZHEIMER)


Detailed regional and laminar analyses of the neuropathological lesions in Alzheimer’s disease (AD) indicate that subsets of neocortical and hippocampal neurons are compromised, leading to the disruption of corticocortical pathways which in turn may subserve the dementia observed clinically Previous analyses of the morphologic and biochemical characteristics of the neurons that are vulnerable to degeneration and neurofibrillary tangle formation in AD have demonstrated that a subpopulation of pyramidal neurons containing high concentration of neurofilament protein in layers III and V of neocortical association areas is dramatically affected in AD, whereas these neurons are relatively spared in primary sensory and motor cortices. In addition, in normal brains, these cells exhibit highly specific regional and laminar distribution patterns in the neocortex and their morphology and location suggest that they are the cells of origin of long corticocortical projections. However, the degree to which these neurons contribute of different long cortical pathways in the primate brain is not known. To explore this issue, we performed an extensive quantitative analysis of more than 30 corticocortical pathways in the monkey neocortex, combining tract-tracing and immunohistochemistry. These studies revealed that the proportion of neurofilament protein-containing neurons varies substantially among corticocortical projections, with low numbers of immunoreactive neurons in the limbic and short corticocortical connections (0–30%), intermediate numbers in callosal connections (30–45%), and very high numbers (60–100%) in long association pathways linking polymodal regions. In the visual system, there are higher proportions of immunoreactive neurons in the occipitoparietal pathway (up to 85 %) compared to the occipitotemporal pathway (up to 40 %). Interestingly, a similar pattern is observed in the visual pathways for the kainate receptor sub-unit proteins GluR5/6/7, whereas the AMPA GluR2/4 and NMDAR1 subunits are ubiquitous, indicating a possible link between excitotoxic mechanisms and the presence of neurofilament protein and specific combination of glutamate receptor subunits in certain populations in AD. In addition, combined cell loading, tract-tracing and immunohistochemistry analyses demonstrated that there is a considerable degree of regional and laminar variability among the different corticocortical projections, not only in terms of neurofilament protein content but also regarding cellular morphology. Several studies have shown that neurofilament protein is involved in the formation of neuropathological lesions in several neurodegenerative disorders. Although neurofilament protein is a useful and reliable marker of neuronal vulnerability in AD, the differential distribution of neuropathologic lesions in dementing illnesses and the apparent discrepancies observed in neurofilament protein and glutamate receptor subunit proteins expression among corticocortical projections suggest that the phenotype of the affected cells in neurodegenerative disorders is related not solely to the presence of certain molecules but to morphological features and connectivity constraints as well. Comparison of results from the macaque monkey analyses with quantitative neuropathological data in human will be important to characterize further the degree to which the vulnerable neurons in AD are homologous to the neurons furnishing corticocortical connections in nonhuman primates. Such comparative studies may also provide valuable information on the involvement of different sets of neurochemically identifiable neuronal populations in the course of various neurodegenerative illnesses.


Macaque Monkey Middle Temporal Posterior Cortical Atrophy Laminar Distribution Neurochemical Characteristic 
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© Springer-Verlag Berlin Heidelberg 1997

Authors and Affiliations

  1. 1.Fishberg Research Center for NeurobiologyMount Sinai School of MedicineNew YorkUSA

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