David A. DeWitt
Case Western Reserve University
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Featured researches published by David A. DeWitt.
Experimental Neurology | 1998
David A. DeWitt; George Perry; Mark L. Cohen; Catherine Doller; Jerry Silver
We have developed an in vitro model in which isolated senile plaque (SP) cores are presented to rat microglial cells in culture. Microglia rapidly phagocytosed, broke apart, and cleared SP cores. However, when cocultured with astrocytes, microglial phagocytosis was markedly suppressed, allowing the SPs to persist. Suppression of phagocytosis by astrocytes appears to be a general phenomena since microglia in the presence of astrocytes showed reduced capacity to phagocytose latex beads as well. The astrocyte effect on microglia is related in part to a diffusible factor(s) since astrocyte- but not fibroblast-conditioned media also reduced phagocytosis. These results suggest that while microglia have the capacity to phagocytose and remove SPs, astrocytes which lie in close association to microglia may help prevent the efficient clearance of SP material allowing them to persist in Alzheimers disease.
Experimental Neurology | 1993
David A. DeWitt; Jerry Silver; David R. Canning; George Perry
Chondroitin sulfate proteoglycans (CSPG) are extracellular matrix proteins inhibitory to neurite outgrowth in vitro and correlated with decreased neurite outgrowth after CNS injury. Previously, heparan sulfate proteoglycan and dermatan sulfate proteoglycan have been shown to be associated with senile plaques (SPs) and neurofibrillary tangles (NFTs) but CSPG was not. In an immunocytochemical study, three monoclonal antibodies to different sulfation states of the chondroitin glycosaminoglycan were used to localize CSPG in cases of Alzheimers disease. Chondroitin 4-sulfate was found in both SPs and NFTs. An antibody to unsulfated chondroitin strongly immunostained intracellular NFTs and the dystrophic neurites of SPs. Chondroitin 6-sulfate was found in NFTs and the area around SPs. These results suggest that CSPG, in addition or as an alternative to beta-amyloid protein, could be responsible for the regression of neurites around senile plaques in Alzheimers disease.
Experimental Neurology | 1993
David R. Canning; Robert J. Mckeon; David A. DeWitt; George Perry; Jerome R. Wujek; Robert Frederickson; Jerry Silver
Pathological lesions in the brains of patients with Alzheimers disease (AD) are characterized by dense deposits of the protein beta-amyloid. The link between the deposition of beta-amyloid in senile plaques and AD-associated pathology is, at present, controversial since there have been conflicting reports on whether the 39-43 amino acid beta-amyloid sequence is toxic or trophic to neurons. In this report, we show that beta-amyloid peptide when presented as an insoluble substrate which mimics its conformation in vivo can induce cortical glial cells in vitro and in vivo to locally deposit chondroitin sulfate containing proteoglycan. In vitro the proteoglycan-containing matrix deposited by glia on beta-amyloid blocks the usual ability of the peptide to allow cortical neurons to adhere and grow. Chondroitin sulfate-containing proteoglycan was also found in senile plaques of human AD tissue. We suggest that an additional effect of beta-amyloid in the brain, which compounds the direct effects of beta-amyloid on neurons, is mediated by the stimulation of astroglia to become reactive. Once in the reactive state, glial cells deposit large amounts of growth-inhibitory molecules within the neuropil which could impair neuronal process survival and regeneration leading to neurite retraction and/or dystrophy around senile plaques in AD.
Brain Research | 1994
David A. DeWitt; Peggy L. Richey; Darja Praprotnik; Jerry Silver; George Perry
Previously, we showed three differentially sulfated forms of chondroitin sulfate proteoglycans (CSPG) associated with senile plaques, astrocytes and neurofibrillary tangles in Alzheimers disease. Here, monoclonal antibodies were used to demonstrate CSPGs in other neurodegenerative diseases. CSPGs were found associated with inclusions of Parkinsons, diffuse Lewy body, Picks diseases, and progressive supranuclear palsy. Reacting astrocytes in each of these neurodegenerative diseases and Huntingtons disease showed immunoreactivity for CSPG. CSPG distribution in a variety of neurodegenerative diseases suggests that similar mechanisms may be involved in the accumulation of proteoglycans in a number of filamentous inclusions.
Experimental Neurology | 1996
David A. DeWitt; Jerry Silver
Although neuronal pathology and synaptic loss are salient features of Alzheimers disease (AD), the underlying mechanisms involved are unknown. Using double-immunolabeled preparations, we found that both the density and the total lengths of axons are decreased within the A(beta)-containing area of senile plaques (SP) in comparison with the adjacent neuropil. These observations suggest that axotomy is occurring in the vicinity of the SP which could account for the synaptic loss. Since A(beta) in solution has been shown to be neurotoxic in vitro, we tested whether intact SP cores isolated from AD brain were equally detrimental when presented to retinal ganglion neurons. Surprisingly, SPs did not appear to be toxic or even repulsive to neurons since they adhered well and elaborated axons which wrapped tightly around the SP core. In the presence of cortical astrocytes, however, neurons appeared to avoid SP cores. We found that astrocytes accumulate and deposit chondroitin sulfate proteoglycans (CSPGs) around SP cores in vitro in a pattern similar to that observed around SPs in Alzheimers disease brain. Neuronal avoidance of astrocyte-conditioned SP cores could be due to the axon outgrowth inhibitory nature of CSPGs. These results suggest that astrocytic reaction to SPs, including increased CSPGs, may facilitate the decreased axon density and synaptic loss in AD brain. Moreover, the similarities between swollen axon endings following axotomy in trauma and the dystrophic neurites of the SP suggest that dystrophic neurites in AD may be exhibiting regenerative failure rather than aberrant sprouting.
Neurobiology of Disease | 2001
Othman Ghribi; Mary M. Herman; Michael S. Forbes; David A. DeWitt; John Savory
Archive | 2005
David A. DeWitt; Rudy J. Castellani; George Perry; Mark A. Smith
Neurobiology of Aging | 2004
David A. DeWitt; Jennifer Hurd; Othman Ghribi; Nena Fox; Kathy J. Griffioen; John Savory
Neurobiology of Aging | 2000
Alan D. Snow; Joel Cummings; Paula Y. Choi; Catherine Ngo; Thomas N. Wight; George Perry; David A. DeWitt; Gerardo Castillo
Neurobiology of Aging | 2000
Othman Ghribi; David A. DeWitt; Michael S. Forbes; Mary M. Herman; John Savory