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Hippocampal administration of chondroitinase ABC increases plaque-adjacent synaptic marker and diminishes amyloid burden in aged APPswe/PS1dE9 mice.

Howell MD, Bailey LA, Cozart MA, Gannon BM, Gottschall PE - Acta Neuropathol Commun (2015)

Bottom Line: Increasing evidence indicates that lecticans may also play a role in synaptic plasticity related to memory, especially associated with aging.In human superior frontal gyrus, levels of the brain-specific lectican, brevican, were significantly elevated in AD compared to non-cognitively impaired subjects, with a trend toward an increase in tissue from subjects with mild cognitive impairment.Since the hippocampus undergoes changes in synaptic plasticity early in the disease process, it could be possible that removal of lecticans or inhibition of their signaling pathways could prolong plasticity in patients early in the disease process, and delay cognitive decline of AD progression.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Sciences, Iowa State University, 2069 Veterinary Medicine, Ames, IA, 50011, USA. mhowell@iastate.edu.

ABSTRACT

Introduction: Substantial data has shown that the lectican group of chondroitin sulfate proteoglycans are involved in inhibition of axonal plasticity in response to injury in the central nervous system. Increasing evidence indicates that lecticans may also play a role in synaptic plasticity related to memory, especially associated with aging. A recent study has shown that lectican expression is elevated at a young age in the APPswe/PS1dE9 mouse model and Alzheimer's disease (AD) and hippocampal treatment with chondroitinase ABC reversed a loss of contextual fear memory and restored long-term potentiation. The purpose of this study was to examine the presence of a synaptic lectican in AD tissue, determine if amyloid-β (Aβ) binds to lecticans purified from brain tissue, and examine how treatment of the same AD model with chondroitinase ABC would influence plaque burden and the density of the synaptic marker synaptophysin around plaques.

Results: In human superior frontal gyrus, levels of the brain-specific lectican, brevican, were significantly elevated in AD compared to non-cognitively impaired subjects, with a trend toward an increase in tissue from subjects with mild cognitive impairment. In vitro immunoprecipitation studies showed that brevican binds to oligomeric and fibrillar Aβ1-42, and less so to monomeric Aβ1-42. Intrahippocampal injection of 15 months APPswe/PS1dE9 mice with chondroitinase ABC resulted in a reduction of Aβ burden in the stratum lacunosum moleculare and a reversal of the loss of synaptic density surrounding plaques in the same region.

Conclusions: It is possible that lecticans, particularly brevican, inhibit synaptic plasticity in this model of AD. Since the hippocampus undergoes changes in synaptic plasticity early in the disease process, it could be possible that removal of lecticans or inhibition of their signaling pathways could prolong plasticity in patients early in the disease process, and delay cognitive decline of AD progression.

No MeSH data available.


Related in: MedlinePlus

ChABC injection increases density of synaptophysin surrounding Aβ plaques in the slm. aa. freehand rings were drawn around three regions of an amyloid plaque (inner, middle and outer). ab. rings were transferred to the identical location on the synaptophysin image and density measured in each ring. ac. identically drawn rings were moved to an adjacent, non-plaque region and synaptophysin density measured. b. quantitative density measurements of synaptophysin immunoreactivity around plaques in slm of 15 months old APPswe/PS1dE9 mice. Measurements were made in the slm after ChABC injection on the (c) contralateral, non-injected hemisphere and the (d) injected, ipsilateral side. The y-axis term “Proportion of non-plaque density” refers to the ratio of synaptophysin density of the plaque region divided by the synaptophysin density of the non-plaque region. This proportion was calculated for the “inner”, “middle” and “outer” regions of the plaque. Note there was a significant loss of synaptophysin immunoreactivity between the outer and middle plaque layers on the contralateral (c) but not inpsilateral, ChABC-injected side (d). For (b) n = 5 mice, for (c) and (d) n = 7 mice, * p < 0.05; ***p < 0.001
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Fig5: ChABC injection increases density of synaptophysin surrounding Aβ plaques in the slm. aa. freehand rings were drawn around three regions of an amyloid plaque (inner, middle and outer). ab. rings were transferred to the identical location on the synaptophysin image and density measured in each ring. ac. identically drawn rings were moved to an adjacent, non-plaque region and synaptophysin density measured. b. quantitative density measurements of synaptophysin immunoreactivity around plaques in slm of 15 months old APPswe/PS1dE9 mice. Measurements were made in the slm after ChABC injection on the (c) contralateral, non-injected hemisphere and the (d) injected, ipsilateral side. The y-axis term “Proportion of non-plaque density” refers to the ratio of synaptophysin density of the plaque region divided by the synaptophysin density of the non-plaque region. This proportion was calculated for the “inner”, “middle” and “outer” regions of the plaque. Note there was a significant loss of synaptophysin immunoreactivity between the outer and middle plaque layers on the contralateral (c) but not inpsilateral, ChABC-injected side (d). For (b) n = 5 mice, for (c) and (d) n = 7 mice, * p < 0.05; ***p < 0.001

Mentions: Sections to measure synaptic density surrounding plaques in the slm were stained with anti-Aβ and anti-synaptophysin with the same secondary antibodies. Synaptophysin density was measured with similar distribution of sections. Plaques were identified in the slm and images were adjusted for brightness and contrast that was used in an identical manner for every section. The Aβ image was magnified to 150 % of the original; using the freehand selection tool on Image J, a freehand shape was drawn around the most intense region of the plaque. Once complete, the synaptophysin image was selected, and the “Restore Selection” command (Edit→Selection→Restore Selection) was used to move the freehand drawing onto the synaptophysin image in the identical location and density measured. The drawing was then moved to a similar non-plaque area in the un-injected hippocampus, density measured, and the density of the plaque was divided by the density of the non-plaque region. This procedure was then repeated for a region outside the intense region of the plaque and then a region that is ½ the width of the distance between the two previous freehand drawings. Thus, the y-axis term “Proportion of non-plaque density” in Fig. 5 refers to the ratio of synaptophysin density of the plaque region divided by the synaptophysin density of the non-plaque region. This proportion was calculated for the “inner”, “middle” and “outer” regions of the plaque.


Hippocampal administration of chondroitinase ABC increases plaque-adjacent synaptic marker and diminishes amyloid burden in aged APPswe/PS1dE9 mice.

Howell MD, Bailey LA, Cozart MA, Gannon BM, Gottschall PE - Acta Neuropathol Commun (2015)

ChABC injection increases density of synaptophysin surrounding Aβ plaques in the slm. aa. freehand rings were drawn around three regions of an amyloid plaque (inner, middle and outer). ab. rings were transferred to the identical location on the synaptophysin image and density measured in each ring. ac. identically drawn rings were moved to an adjacent, non-plaque region and synaptophysin density measured. b. quantitative density measurements of synaptophysin immunoreactivity around plaques in slm of 15 months old APPswe/PS1dE9 mice. Measurements were made in the slm after ChABC injection on the (c) contralateral, non-injected hemisphere and the (d) injected, ipsilateral side. The y-axis term “Proportion of non-plaque density” refers to the ratio of synaptophysin density of the plaque region divided by the synaptophysin density of the non-plaque region. This proportion was calculated for the “inner”, “middle” and “outer” regions of the plaque. Note there was a significant loss of synaptophysin immunoreactivity between the outer and middle plaque layers on the contralateral (c) but not inpsilateral, ChABC-injected side (d). For (b) n = 5 mice, for (c) and (d) n = 7 mice, * p < 0.05; ***p < 0.001
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Fig5: ChABC injection increases density of synaptophysin surrounding Aβ plaques in the slm. aa. freehand rings were drawn around three regions of an amyloid plaque (inner, middle and outer). ab. rings were transferred to the identical location on the synaptophysin image and density measured in each ring. ac. identically drawn rings were moved to an adjacent, non-plaque region and synaptophysin density measured. b. quantitative density measurements of synaptophysin immunoreactivity around plaques in slm of 15 months old APPswe/PS1dE9 mice. Measurements were made in the slm after ChABC injection on the (c) contralateral, non-injected hemisphere and the (d) injected, ipsilateral side. The y-axis term “Proportion of non-plaque density” refers to the ratio of synaptophysin density of the plaque region divided by the synaptophysin density of the non-plaque region. This proportion was calculated for the “inner”, “middle” and “outer” regions of the plaque. Note there was a significant loss of synaptophysin immunoreactivity between the outer and middle plaque layers on the contralateral (c) but not inpsilateral, ChABC-injected side (d). For (b) n = 5 mice, for (c) and (d) n = 7 mice, * p < 0.05; ***p < 0.001
Mentions: Sections to measure synaptic density surrounding plaques in the slm were stained with anti-Aβ and anti-synaptophysin with the same secondary antibodies. Synaptophysin density was measured with similar distribution of sections. Plaques were identified in the slm and images were adjusted for brightness and contrast that was used in an identical manner for every section. The Aβ image was magnified to 150 % of the original; using the freehand selection tool on Image J, a freehand shape was drawn around the most intense region of the plaque. Once complete, the synaptophysin image was selected, and the “Restore Selection” command (Edit→Selection→Restore Selection) was used to move the freehand drawing onto the synaptophysin image in the identical location and density measured. The drawing was then moved to a similar non-plaque area in the un-injected hippocampus, density measured, and the density of the plaque was divided by the density of the non-plaque region. This procedure was then repeated for a region outside the intense region of the plaque and then a region that is ½ the width of the distance between the two previous freehand drawings. Thus, the y-axis term “Proportion of non-plaque density” in Fig. 5 refers to the ratio of synaptophysin density of the plaque region divided by the synaptophysin density of the non-plaque region. This proportion was calculated for the “inner”, “middle” and “outer” regions of the plaque.

Bottom Line: Increasing evidence indicates that lecticans may also play a role in synaptic plasticity related to memory, especially associated with aging.In human superior frontal gyrus, levels of the brain-specific lectican, brevican, were significantly elevated in AD compared to non-cognitively impaired subjects, with a trend toward an increase in tissue from subjects with mild cognitive impairment.Since the hippocampus undergoes changes in synaptic plasticity early in the disease process, it could be possible that removal of lecticans or inhibition of their signaling pathways could prolong plasticity in patients early in the disease process, and delay cognitive decline of AD progression.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Sciences, Iowa State University, 2069 Veterinary Medicine, Ames, IA, 50011, USA. mhowell@iastate.edu.

ABSTRACT

Introduction: Substantial data has shown that the lectican group of chondroitin sulfate proteoglycans are involved in inhibition of axonal plasticity in response to injury in the central nervous system. Increasing evidence indicates that lecticans may also play a role in synaptic plasticity related to memory, especially associated with aging. A recent study has shown that lectican expression is elevated at a young age in the APPswe/PS1dE9 mouse model and Alzheimer's disease (AD) and hippocampal treatment with chondroitinase ABC reversed a loss of contextual fear memory and restored long-term potentiation. The purpose of this study was to examine the presence of a synaptic lectican in AD tissue, determine if amyloid-β (Aβ) binds to lecticans purified from brain tissue, and examine how treatment of the same AD model with chondroitinase ABC would influence plaque burden and the density of the synaptic marker synaptophysin around plaques.

Results: In human superior frontal gyrus, levels of the brain-specific lectican, brevican, were significantly elevated in AD compared to non-cognitively impaired subjects, with a trend toward an increase in tissue from subjects with mild cognitive impairment. In vitro immunoprecipitation studies showed that brevican binds to oligomeric and fibrillar Aβ1-42, and less so to monomeric Aβ1-42. Intrahippocampal injection of 15 months APPswe/PS1dE9 mice with chondroitinase ABC resulted in a reduction of Aβ burden in the stratum lacunosum moleculare and a reversal of the loss of synaptic density surrounding plaques in the same region.

Conclusions: It is possible that lecticans, particularly brevican, inhibit synaptic plasticity in this model of AD. Since the hippocampus undergoes changes in synaptic plasticity early in the disease process, it could be possible that removal of lecticans or inhibition of their signaling pathways could prolong plasticity in patients early in the disease process, and delay cognitive decline of AD progression.

No MeSH data available.


Related in: MedlinePlus