β-Amyloid of Alzheimer's Disease Induces Reactive Gliosis That Inhibits Axonal Outgrowth

Canning, David R.; McKeon, Robert J.; DeWitt, David A.; Perry, George; Wujek, Jerome R.; Frederickson, Robert C.A.; Silver, Jerry

doi:10.1006/exnr.1993.1199

Cited by 145 publications

(74 citation statements)

References 33 publications

(44 reference statements)

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“…We have found in additional studies that astrocytes accumulate CSPGs in response to AfJ (6), therefore, glia may be the source for some of the CSPGs. However, since primarily intraneuronal NFTs were also stained, a potential source of CSPG could be neuronal.…”

Section: Discussionmentioning

confidence: 72%

Chondroitin Sulfate Proteoglycans Are Associated with the Lesions of Alzheimer's Disease

DeWitt

Silver

Canning

et al. 1993

Experimental Neurology

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176

107

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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 Alzheimer's 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 ~-amyloid protein, could be responsible for the regression of neurites around senile plaques in Alzheimer's disease.

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Section: Discussionmentioning

confidence: 72%

Chondroitin Sulfate Proteoglycans Are Associated with the Lesions of Alzheimer's Disease

DeWitt

Silver

Canning

et al. 1993

Experimental Neurology

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176

107

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“…69, No. 4, /997 Aß that are potentially relevant to the promotion of AD neuropathology include induction of astroglial (Canning et al, 1993;Pike et al, 1994) and microglial (Araujo and Cotman, 1992) reactivity, cerebrovasculature impairment (Thomas et al, 1996; Van Nostrand et aI., 1996), activation of inflammatory cascades (McGeer and McGeer, 1995;Rogers et al, 1996), and, perhaps most significant, direct and indirect induction of neuronal degeneration . If Aß does play a primary role in AD etiology, clarifying the mechanism(s) of Aß bioactivity is of great importance in terms of both understanding the disease and developing therapeutic interventions.…”

Section: Discussionmentioning

confidence: 99%

β‐Amyloid Neurotoxicity In Vitro: Evidence of Oxidative Stress but Not Protection by Antioxidants

Pike

Ramezan‐Arab

Cotman

1997

Journal of Neurochemistry

120

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Recent data from several groups suggest that the primary mechanism of ß-amyloid neurotoxicity may be mediated by reactive oxygen species. To evaluate this hypothesis, we first compared the efficacy of antioxidant agents in preventing toxicity caused by oxidative insults (iron, hydrogen peroxide, and tert-butyl hydroperoxide) and ß-amyloid peptides in cultured rat hippocampal neurons. Tested antioxidants (propyl gallate, Trolox, probucol, and promethazine) generally provided significant protection against oxidative insults but not ß-amyloid peptides. Next, we examined whether ß-amyloid causes oxidative stress, by comparing levels of lipid peroxidation after exposure to either iron or ß-amyloid. In a cell-free system, iron but not ß-amyloid generated lipid peroxidation. In culture, both insults caused rapid increases in lipid peroxidation, with iron inducing higher levels at later time points. Pretreatment with the antioxidant probucol significantly reduced lipid peroxidation caused by both insults but only attenuated iron toxicity, suggesting that lipid peroxidation does not contribute directly to cell death induced by ß-amyloid. Finally, we observed that increasing basal levels of oxidative stress by pretreating cultures with subtoxic doses of iron significantly increased neuronal vulnerability to ß-amyloid. The ability of ß-amyloid to induce oxidative stress and the demonstration that oxidative stress potentiatesß-amyloid toxicity support the clinical use of antioxidants for AD. However, these data do not support the theory that the primary mechanism of ß-amyloid toxicity involves oxidative pathways, indicating a continued need to identify additional cellular responses to ß-amyloid that underlie its neurodegenerative actions. Key Words: ß-AmyloidAlzheimer's disease-Antioxidants-Free radicalsLipid peroxidation-Oxidative stress. J. Neurochem. 69,1601Neurochem. 69, -1611Neurochem. 69, (1997.sociated with neuritic dystrophy and reactive glia (Wisniewski and Terry, 1973;Probst et al., 1987;Rozemuller et al., 1989). The Aß hypothesis is further supported by our recent demonstration that the extent of Aß deposition in entorhinal cortex correlates with cognitive decline in AD patients (r '-.~-O.9) better than other pathological indices (Cummings et al., 1996). Causal contributions of Aß to AD neurodegeneration are also implied by analyses of genetic mutations linked to familial forms of AD. Specifically, several rare autosomal dominant mutations in the Aß precursor protein gene on chromosome 21 and relatively more prevalent mutations in the presenilin-1 and presenilin-2 genes on chromosomes 14 and 1, respectively, appear to precipitate AD at least in part by causing significant increases in either the overall production of Aß or the levels of particularly amyloidogenic X-42/43 Aß species (for review, see Selkoe, 1996).An important contributory role of Aß in AD neurodegeneration is also supported by in vitro and in vivo experimental paradigms that have demonstrated neurodegenerative actions of Aß peptides (for...

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“…Several in vitro assays, in which mature astrocytes were induced to be highly reactive, have confirmed that upregulated proteoglycans within the complex ECM that is made by reactive astroglia inhibit axonal outgrowth 68,73,75,76 . To further demonstrate that the GAG portion of CSPGs is inhibitory to neurite outgrowth, chondroitinase -an enzyme extracted from the bacterium Proteus vulgaris that selectively removes a large portion of the CSPG GAG side chain and renders CSPGs less inhibitory (see later in text) -was applied to mature glial 'scar-in-a-dish' explants (see BOX 1).…”

Section: Dorsal Root Ganglionmentioning

confidence: 96%

Regeneration beyond the glial scar

2004

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β-Amyloid of Alzheimer's Disease Induces Reactive Gliosis That Inhibits Axonal Outgrowth

Cited by 145 publications

References 33 publications

Chondroitin Sulfate Proteoglycans Are Associated with the Lesions of Alzheimer's Disease

Chondroitin Sulfate Proteoglycans Are Associated with the Lesions of Alzheimer's Disease

β‐Amyloid Neurotoxicity In Vitro: Evidence of Oxidative Stress but Not Protection by Antioxidants

Regeneration beyond the glial scar

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