Microglial reactivity correlates to the density and the myelination of the anterogradely degenerating axons and terminals following perforant path denervation of the mouse fascia dentata

Jensen, Marina Bergen; Hegelund, I.V.; Poulsen, Frantz Rom; Owens, Trevor; Zimmer, Jens; Finsen, Bente

doi:10.1016/s0306-4522(99)00139-6

Cited by 50 publications

(61 citation statements)

References 43 publications

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“…Results are given as mean Ϯ SD. lecular layer at 7 days post lesion 41 and that microglial clearance of myelin debris is stimulated by infiltrating T MBP , 35 we also investigated the clearance of CNP ϩ myelin debris in PP-lesioned T PLP , T OVA , and naïve mice (see Supplemental Figure S2A at http://ajp.amjpathol. org).…”

Section: Myelin-reactive T Cells Enhance Clearance Of Myelin Debrismentioning

confidence: 99%

Stimulation of Adult Oligodendrogenesis by Myelin-Specific T Cells

Nielsen

Toft-Hansen

Lambertsen

et al. 2011

The American Journal of Pathology

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In multiple sclerosis (MS), myelin-specific T cells are normally associated with destruction of myelin and axonal damage. However, in acute MS plaque, remyelination occurs concurrent with T-cell infiltration, which raises the question of whether T cells might stimulate myelin repair. We investigated the effect of myelin-specific T cells on oligodendrocyte formation at sites of axonal damage in the mouse hippocampal dentate gyrus. Infiltrating T cells specific for myelin proteolipid protein stimulated proliferation of chondroitin sulfate NG2-expressing oligodendrocyte precursor cells early after induction via axonal transection, resulting in a 25% increase in the numbers of oligodendrocytes. In contrast, T cells specific for ovalbumin did not stimulate the formation of new oligodendrocytes. In addition, infiltration of myelinspecific T cells enhanced the sprouting response of calretinergic associational/commissural fibers within the dentate gyrus. These results have implications for the perception of MS pathogenesis because they show that infiltrating myelin-specific T cells can stimulate oligodendrogenesis in the adult central nervous system. T cell infiltration, demyelination, and axonal damage are central pathologic features of multiple sclerosis (MS). Whereas the primary immune attack on oligodendrocytes and myelin is effected by T cells, 1,2 remyelination occurs in acute plaques, also in the presence of T cells. 3,4 Remyelination depends on chondroitin sulfate NG2-expressing adult oligodendrocyte precursor cells (OPCs). 5,6 OPCs retain the capacity to proliferate and differentiate into myelinating oligodendrocytes in response to toxic or inflammatory demyelination 7-9 and other forms of central nervous system (CNS) injury such as ischemia, 10 spinal cord injury, 11,12 axonal lesions, 13,14 and inflammation. 15 During differentiation, OPCs downregulate NG2 as cells acquire markers of mature oligodendrocytes such as 2=,3=-cyclic nucleotide 3=-phosphodiesterase (CNP). 16 The axonal damage that occurs within and distal to the acute MS lesion can be modeled in the hippocampal dentate gyrus by transection of the perforant pathway (PP), resulting in degeneration of the PP axons and their myelin sheaths in the outer part of the molecular layer. [17][18][19] PP lesions also induce proliferation of OPCs, which results in formation of new oligodendrocytes. 14 These newly formed oligodendrocytes are presumed to myelinate the axonal sprouts that extend from other afferent fiber systems in the dentate gyrus 20,21 such as the associational/commissural afferents from the calretinergic hilar mossy cells. 20,22,23 Indeed, in stratum radiatum of the hippocampal CA3 region, lesion-induced axonal sprouting is associated with formation of more oligodendrocytes and more myelin. 24 Because remyelination ultimately fails in MS, 25 it is assumed that autoimmune demyelination reduces the capacity for myelin repair. 26,27 We investigated the effect of myelin-specific T cells on the formation of oligodendrocytes in the dentate gyrus of ...

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Section: Myelin-reactive T Cells Enhance Clearance Of Myelin Debrismentioning

confidence: 99%

Stimulation of Adult Oligodendrogenesis by Myelin-Specific T Cells

Nielsen

Toft-Hansen

Lambertsen

et al. 2011

The American Journal of Pathology

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“…Thus, the initiation of a septodentate growth response seems to rely on factors additional to the NGF. After an entorhinal lesion, a cascade of cellular events is instigated, including the degeneration of neuronal elements (Steward, 1992;Shi and Stanfield, 1996;Jensen et al, 1999), microglial and astrocytic activation (Jensen et al, 1994), and the increased synthesis of extracellular matrix proteins (Deller et al, 2001). In this context, the degeneration of presynaptic elements may be particularly salient for the induction of sprouting, as suggested by studies indicating that a delay in the onset of Wallerian degeneration after a perforant path lesion produces a parallel delay in the onset of septodentate sprouting (Steward, 1992;Shi and Stanfield, 1996).…”

Section: Discussionmentioning

confidence: 99%

Adeno-Associated Virus Vector Expressing Nerve Growth Factor Enhances Cholinergic Axonal Sprouting after Cortical Injury in Rats

et al. 2003

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Nerve growth factor (NGF) is known to promote both the survival of cholinergic neurons after injury and the regeneration of damaged cholinergic axons. Recent evidence has implicated NGF in the regulation of cholinergic axonal sprouting by intact neurons projecting to the hippocampus of rats, sustaining a lesion of the entorhinal cortex. We explored the possibility that NGF may regulate this lesioninduced cholinergic sprouting by injecting recombinant adeno-associated virus (rAAV) vector expressing NGF and green fluorescent protein (GFP) into the dentate gyrus of rats that were subsequently given unilateral entorhinal lesions. Sprague Dawley rats were unilaterally injected with (1) rAAV vector expressing NGF and GFP or (2) rAAV vector expressing GFP. Fourteen days after injection, the animals received lesions of the entorhinal area ipsilateral to the virus injection. Four days after lesion, GFP expression and the septodentate sprouting response in the dentate gyrus were assessed. Optical densitometric analyses revealed a significant increase in acetylcholinesterase label (a marker for cholinergic septodentate sprouting) in the ipsilateral outer molecular layer of the dentate gyrus in rats injected with rAAV vector expressing NGF. Thus, NGF-expressing rAAV vector enhanced the sprouting response of intact cholinergic neurons after unilateral entorhinal lesions in rats.

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“…The nosebar was set at Ϫ3 mm. A wire knife (Kopf Instruments) was inserted at an angle of 15°r ostrally and 10°laterally, and 3.4 mm ventral to the meninges, the knife was unfolded and the entorhinodentate perforant path projection was sectioned by retracting the knife 3.2 mm (24,29).…”

Section: Entorhinal Cortex Lesioningmentioning

confidence: 99%

NF-κB-Driven STAT2 and CCL2 Expression in Astrocytes in Response to Brain Injury

Khorooshi

Babcock

Owens

2008

The Journal of Immunology

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Tissue response to injury includes expression of genes encoding cytokines and chemokines. These regulate entry of immune cells to the injured tissue. The synthesis of many cytokines and chemokines involves NF-κB and signal transducers and activators of transcription (STAT). Injury to the CNS induces glial response. Astrocytes are the major glial population in the CNS. We examined expression of STATs and the chemokine CCL2 and their relationship to astroglial NF-κB signaling in the CNS following axonal transection. Double labeling with Mac-1/CD11b and glial fibrillary acidic protein revealed that STAT2 up-regulation and phosphorylation colocalized exclusively to astrocytes, suggesting the involvement of STAT2 activating signals selectively in astroglial response to injury. STAT1 was also up-regulated and phosphorylated but not exclusively in astrocytes. Both STAT2 up-regulation and phosphorylation were NF-κB -dependent since they did not occur in the lesion-reactive hippocampus of transgenic mice with specific inhibition of NF-κB activation in astrocytes. We further showed that lack of NF-κB signaling significantly reduced injury-induced CCL2 expression as well as leukocyte infiltration. Our results suggest that NF-κB signaling in astrocytes controls expression of both STAT2 and CCL2, and thus regulates infiltration of leukocytes into lesion-reactive hippocampus after axonal injury. Taken together, these findings indicate a central role for astrocytes in directing immune-glial interaction in the CNS injury response.

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Microglial reactivity correlates to the density and the myelination of the anterogradely degenerating axons and terminals following perforant path denervation of the mouse fascia dentata

Cited by 50 publications

References 43 publications

Stimulation of Adult Oligodendrogenesis by Myelin-Specific T Cells

Stimulation of Adult Oligodendrogenesis by Myelin-Specific T Cells

Adeno-Associated Virus Vector Expressing Nerve Growth Factor Enhances Cholinergic Axonal Sprouting after Cortical Injury in Rats

NF-κB-Driven STAT2 and CCL2 Expression in Astrocytes in Response to Brain Injury

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