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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

Western blot of human brevican from superior frontal gyrus of subjects with NCI (no cognitive impairment), MCI (mild cognitive impairment) and AD (Alzheimer’s disease). a Brevican blot of one lane from each group with intact brevican indicated by the arrow and GAPDH inset for normalization. b Quantification of intact brevican band density as a proportion of GAPDH density. Data were subject to one way ANOVA followed by Bonferroni multiple comparison test. Level of AD brevican is significantly elevated (p < 0.05) compared to NCI; (NCI n = 14, MCI n = 10, AD n = 14)
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Fig1: Western blot of human brevican from superior frontal gyrus of subjects with NCI (no cognitive impairment), MCI (mild cognitive impairment) and AD (Alzheimer’s disease). a Brevican blot of one lane from each group with intact brevican indicated by the arrow and GAPDH inset for normalization. b Quantification of intact brevican band density as a proportion of GAPDH density. Data were subject to one way ANOVA followed by Bonferroni multiple comparison test. Level of AD brevican is significantly elevated (p < 0.05) compared to NCI; (NCI n = 14, MCI n = 10, AD n = 14)

Mentions: Increasing evidence has demonstrated that CS-bearing ECM molecules increase with age [20] and are associated with AD [19]. Thus, we assessed brevican content in superior frontal gyrus from no cognitive impairment (NCI), mild cognitive impairment (MCI) and Alzheimer’s disease (AD) subjects using immunoblot (for full blots, see Additional file 2: Figure S1). A clear elevation of intact, full-length brevican core protein content (Fig. 1a, arrow) was observed in AD superior frontal gyrus tissue compared to NCI individuals (Fig. 1a, b). Indeed, brevican in AD frontal gyrus was nearly double that of NCI tissue, and there was a clear trend of increased full length brevican in MCI subjects compared to NCI tissue.Fig. 1


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)

Western blot of human brevican from superior frontal gyrus of subjects with NCI (no cognitive impairment), MCI (mild cognitive impairment) and AD (Alzheimer’s disease). a Brevican blot of one lane from each group with intact brevican indicated by the arrow and GAPDH inset for normalization. b Quantification of intact brevican band density as a proportion of GAPDH density. Data were subject to one way ANOVA followed by Bonferroni multiple comparison test. Level of AD brevican is significantly elevated (p < 0.05) compared to NCI; (NCI n = 14, MCI n = 10, AD n = 14)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4559967&req=5

Fig1: Western blot of human brevican from superior frontal gyrus of subjects with NCI (no cognitive impairment), MCI (mild cognitive impairment) and AD (Alzheimer’s disease). a Brevican blot of one lane from each group with intact brevican indicated by the arrow and GAPDH inset for normalization. b Quantification of intact brevican band density as a proportion of GAPDH density. Data were subject to one way ANOVA followed by Bonferroni multiple comparison test. Level of AD brevican is significantly elevated (p < 0.05) compared to NCI; (NCI n = 14, MCI n = 10, AD n = 14)
Mentions: Increasing evidence has demonstrated that CS-bearing ECM molecules increase with age [20] and are associated with AD [19]. Thus, we assessed brevican content in superior frontal gyrus from no cognitive impairment (NCI), mild cognitive impairment (MCI) and Alzheimer’s disease (AD) subjects using immunoblot (for full blots, see Additional file 2: Figure S1). A clear elevation of intact, full-length brevican core protein content (Fig. 1a, arrow) was observed in AD superior frontal gyrus tissue compared to NCI individuals (Fig. 1a, b). Indeed, brevican in AD frontal gyrus was nearly double that of NCI tissue, and there was a clear trend of increased full length brevican in MCI subjects compared to NCI tissue.Fig. 1

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