Mechanisms of astrocyte-directed neurite guidance

Powell, Elizabeth M.; Meiners, Scott J.; DiProspero, Nicholas A.; Geller, Herbert M.

doi:10.1007/s004410050945

Cited by 74 publications

(31 citation statements)

References 102 publications

(116 reference statements)

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“…For example, the extensive extracellular matrix (ECM) remodeling and cell adhesion changes observed, presumably mediated largely by astrocytes, are similar to processes seen during astrocyte differentiation or cell-type-specific responses to injury (63)(64)(65). Analogous ECM͞adhesion pathways are also used by peripheral cells to suppress cancer cell invasion and metastasis during oncogenesis (66).…”

Section: Discussionmentioning

confidence: 99%

Incipient Alzheimer's disease: Microarray correlation analyses reveal major transcriptional and tumor suppressor responses

Blalock

Geddes

Chen

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

944

853

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The pathogenesis of incipient Alzheimer's disease (AD) has been resistant to analysis because of the complexity of AD and the overlap of its early-stage markers with normal aging. Gene microarrays provide new tools for addressing complexity because they allow overviews of the simultaneous activity of multiple cellular pathways. However, microarray data interpretation is often hindered by low statistical power, high false positives or false negatives, and by uncertain relevance to functional endpoints. Here, we analyzed hippocampal gene expression of nine control and 22 AD subjects of varying severity on 31 separate microarrays. We then tested the correlation of each gene's expression with MiniMental Status Examination (MMSE) and neurofibrillary tangle (NFT) scores across all 31 subjects regardless of diagnosis. These well powered tests revealed a major transcriptional response comprising thousands of genes significantly correlated with AD markers. Several hundred of these genes were also correlated with AD markers across only control and incipient AD subjects (MMSE > 20). Biological process categories associated with incipient AD-correlated genes were identified statistically (EASE program) and revealed up-regulation of many transcription factor͞signaling genes regulating proliferation and differentiation, including tumor suppressors, oligodendrocyte growth factors, and protein kinase A modulators. In addition, up-regulation of adhesion, apoptosis, lipid metabolism, and initial inflammation processes occurred, and down-regulation of protein folding͞me-tabolism͞transport and some energy metabolism and signaling pathways took place. These findings suggest a new model of AD pathogenesis in which a genomically orchestrated up-regulation of tumor suppressor-mediated differentiation and involution processes induces the spread of pathology along myelinated axons. A lzheimer's disease (AD) has received intense study during past decades. Multiple processes have been implicated in AD, notably including abnormal ␤-amyloid (A␤) production (1-7), tau hyperphosphorylation and neurofibrillary tangles (NFTs) (8, 9), synaptic pathology (10-12), oxidative stress (13-15), inflammation (5, 16-19), protein processing or misfolding (20, 21), calcium dyshomeostasis (15,(20)(21)(22)(23)(24)(25)(26), aberrant reentry of neurons into the cell cycle (27, 28), cholesterol synthesis (29, 30), and effects of hormones (23, 31) or growth factors (17, 32). Nevertheless, the pathogenic factors that initiate these processes remain elusive.Several reasons account for the substantial resistance of AD pathogenesis to analysis. One is the vast extent and complexity of the disease, which affects numerous molecules, cells, and systems and impedes attempts to determine which alterations are specifically associated with early pathology. Another is that clinically normal subjects may exhibit considerable AD pathology, blurring criteria for distinguishing subjects with normal aging, mild cognitive impairment, or incipient AD (33-35).We addressed the proble...

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Section: Discussionmentioning

confidence: 99%

Incipient Alzheimer's disease: Microarray correlation analyses reveal major transcriptional and tumor suppressor responses

Blalock

Geddes

Chen

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

944

853

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“…It has indeed been proposed before that up to a certain level of reactivity, astrocytes are not inhibitory for growing axons [65][66][67][68] and might participate in guiding sprouting or regenerating axons in adult CNS, as is the case during development (for review, see Powell and associates 69 ). Several mechanisms have been put forward that may account for the stimulation of axon growth in response to ChABC treatment such as an effect on axons themselves (attenuation of receptor-mediated growth inhibition, or of growth inhibitory downstream signaling in response to CSPG), liberation of matrix bound factors permissive for axonal regeneration, or modification of interactions between CSPG and other matrix molecules, like laminin (for review, see Bradbury and Carter 70 ).…”

Section: Discussionmentioning

confidence: 99%

Astrocytic and Vascular Remodeling in the Injured Adult Rat Spinal Cord after Chondroitinase ABC Treatment

Milbreta

Boxberg

Mailly

et al. 2014

Journal of Neurotrauma

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Upregulation of extracellular chondroitin sulfate proteoglycans (CSPG) is a primary cause for the failure of axons to regenerate after spinal cord injury (SCI), and the beneficial effect of their degradation by chondroitinase ABC (ChABC) is widely documented. Little is known, however, about the effect of ChABC treatment on astrogliosis and revascularization, two important factors influencing axon regrowth. This was investigated in the present study. Immediately after a spinal cord hemisection at thoracic level 8-9, we injected ChABC intrathecally at the sacral level, repeated three times until 10 days post-injury. Our results show an effective cleavage of CSPG glycosaminoglycan chains and stimulation of axonal remodeling within the injury site, accompanied by an extended period of astrocyte remodeling (up to 4 weeks). Interestingly, ChABC treatment favored an orientation of astrocytic processes directed toward the injury, in close association with axons at the lesion entry zone, suggesting a correlation between axon and astrocyte remodeling. Further, during the first weeks post-injury, ChABC treatment affected the morphology of laminin-positive blood vessel basement membranes and vessel-independent laminin deposits: hypertrophied blood vessels with detached or duplicated basement membrane were more numerous than in lesioned untreated animals. In contrast, at later time points, laminin expression increased and became more directly associated with newly formed blood vessels, the size of which tended to be closer to that found in intact tissue. Our data reinforce the idea that ChABC injection in combination with other synergistic treatments is a promising therapeutic strategy for SCI repair.

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“…Astrocytes are thought to be a major source of extracellular matrix (ECM) molecules in the CNS (Pindzola et al, 1993;Powell et al, 1997). These cells, even when differentiated in vitro, have been shown to preserve their capacity to support neuritogenesis, as well as their ability to deposit extracellular matrix (Grierson et al, 1990;Meiners et al, 1995;GarciaAbreu et al, 1995a;Garcia-Abreu et al, 1995b;Martinez and Gomes, 2002).…”

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confidence: 99%

Sialic acid residues on astrocytes regulate neuritogenesis by controlling the assembly of laminin matrices

Freire

Gomes

Jotha-Mattos

et al. 2004

Journal of Cell Science

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In the developing nervous system migrating neurons and growing axons are guided by diffusible and/or substrate-bound cues, such as extracellular matrix-associated laminin. In a previous work we demonstrated that laminin molecules could self-assemble in two different manners, giving rise to matrices that could favor either neuritogenesis or proliferation of cortical precursor cells. We investigated whether the ability of astrocytes to promote neuritogenesis of co-cultivated neurons was modulated by the assembling mode of the laminin matrix secreted by them. We compared the morphologies and neuritogenic potentials of laminin deposited by in vitro-differentiated astrocytes obtained from embryonic or neonatal rat brain cortices. We showed that, while permissive astrocytes derived from embryonic brain produced a flat laminin matrix that remained associated to the cell surface, astrocytes derived from newborn brain secreted a laminin matrix resembling a fibrillar web that protruded from the cell plane. The average neurite lengths obtained for E16 neurons cultured on each astrocyte layer were 198±22 and 123±13 μm, respectively. Analyses of surface-associated electrostatic potentials revealed that embryonic astrocytes presented a pI of -2.8, while in newborn cells this value was -3.8. Removal of the sialic acid groups on the embryonic monolayer by neuraminidase treatment led to the immediate release of matrix-associated laminin. Interestingly, laminin reassembled 1 hour after neuraminidase removal converted to the features of the newborn matrix. Alternatively, treatment of astrocytes with the cholesterol-solubilizing detergent methyl-β-cyclodextrin also resulted in release of the extracellular laminin. To test the hypothesis that sialic-acid-containing lipids localized at cholesterol-rich membrane domains could affect the process of laminin assembly, we devised a cell-free assay where laminin polymerization was carried out over artificial lipid films. Films of either a mixture of gangliosides or pure ganglioside GT1b induced formation of matrices of morpho-functional features similar to the matrices deposited by embryonic astrocytes. Conversely, films of phosphatidylcholine or ganglioside GM1 led to the formation of bulky laminin aggregates that lacked a defined structure. We propose that the expression of negative lipids on astrocytes can control the extracellular polymerization of laminin and, consequently, the permissivity to neuritogenesis of astrocytes during development.

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Mechanisms of astrocyte-directed neurite guidance

Cited by 74 publications

References 102 publications

Incipient Alzheimer's disease: Microarray correlation analyses reveal major transcriptional and tumor suppressor responses

Incipient Alzheimer's disease: Microarray correlation analyses reveal major transcriptional and tumor suppressor responses

Astrocytic and Vascular Remodeling in the Injured Adult Rat Spinal Cord after Chondroitinase ABC Treatment

Sialic acid residues on astrocytes regulate neuritogenesis by controlling the assembly of laminin matrices

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