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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

Injection of ChABC into APPswe/PS1dE9 dorsal hippocampus results in reduced amyloid burden in the stratum lacunosum moleculare (slm). aa. Immunostaining for Aβ (rabbit anti-Aβ 95-2-5) showing whole brain section of ChABC injected APPswe/PS1dE9 mouse hippocampus at low magnification (25x); ab,ab’. Aβ immunostaining of slm on ChABC injected ipsilateral (ab) and contralateral (ab’) sides (100x). ac,ac’. inverted images of (ab and ab’). ad,ad’. PSD-95 staining in the same sections as in (ac,ac’) with slm outlined in blue. ae,ae’. sections from (ac,ac’) thresholded and converted to binary to calculate the area occupied by Aβ. b. Quantitative measurement of area occupied by Aβ in the slm as area occupied by Aβ (left graph; APPswe/PS1dE9 n = 7) and area occupied as per cent of contralateral side (right graph, no ChABC treatment n = 3; ChABC treatment n = 7). Comparison between treatments was made using unpaired Student’s t-test. *p < 0.05 was considered a significant difference between groups
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Fig4: Injection of ChABC into APPswe/PS1dE9 dorsal hippocampus results in reduced amyloid burden in the stratum lacunosum moleculare (slm). aa. Immunostaining for Aβ (rabbit anti-Aβ 95-2-5) showing whole brain section of ChABC injected APPswe/PS1dE9 mouse hippocampus at low magnification (25x); ab,ab’. Aβ immunostaining of slm on ChABC injected ipsilateral (ab) and contralateral (ab’) sides (100x). ac,ac’. inverted images of (ab and ab’). ad,ad’. PSD-95 staining in the same sections as in (ac,ac’) with slm outlined in blue. ae,ae’. sections from (ac,ac’) thresholded and converted to binary to calculate the area occupied by Aβ. b. Quantitative measurement of area occupied by Aβ in the slm as area occupied by Aβ (left graph; APPswe/PS1dE9 n = 7) and area occupied as per cent of contralateral side (right graph, no ChABC treatment n = 3; ChABC treatment n = 7). Comparison between treatments was made using unpaired Student’s t-test. *p < 0.05 was considered a significant difference between groups

Mentions: In APPswe/PSdE9 mice, 18 days after ChABC injection Aβ burden was measured in the stratum lacunosum moleculare (slm), one region of the hippocampus that contains numerous amyloid plaques. The slm was easily recognized when co-staining the sections for PSDS-95 (Figure 4ad and ad’). The reduction in Aβ plaques was observable in the ChABC-treated hemisphere (eg. Figure 4aa). The per cent of the slm occupied by Aβ after thresholding the immunoreactive density (Figure 4ae) was nearly 50 % lower in ChABC treated slm compared to the non-ChABC treated slm hemisphere (Fig. 4b, left graph; p < 0.05). When the ratio of ipsilateral/contralateral was calculated and compared to vehicle-treated APPswe/PS1dE9 mice, there was approximately a 40 % reduction in Aβ burden. Thus, removal of CS for 18 days after injection of ChABC resulted in a significant reduction in the presence of Aβ in the slm hippocampus in APPswe/PS1dE9 mice.Fig. 4


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)

Injection of ChABC into APPswe/PS1dE9 dorsal hippocampus results in reduced amyloid burden in the stratum lacunosum moleculare (slm). aa. Immunostaining for Aβ (rabbit anti-Aβ 95-2-5) showing whole brain section of ChABC injected APPswe/PS1dE9 mouse hippocampus at low magnification (25x); ab,ab’. Aβ immunostaining of slm on ChABC injected ipsilateral (ab) and contralateral (ab’) sides (100x). ac,ac’. inverted images of (ab and ab’). ad,ad’. PSD-95 staining in the same sections as in (ac,ac’) with slm outlined in blue. ae,ae’. sections from (ac,ac’) thresholded and converted to binary to calculate the area occupied by Aβ. b. Quantitative measurement of area occupied by Aβ in the slm as area occupied by Aβ (left graph; APPswe/PS1dE9 n = 7) and area occupied as per cent of contralateral side (right graph, no ChABC treatment n = 3; ChABC treatment n = 7). Comparison between treatments was made using unpaired Student’s t-test. *p < 0.05 was considered a significant difference between groups
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Related In: Results  -  Collection

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Fig4: Injection of ChABC into APPswe/PS1dE9 dorsal hippocampus results in reduced amyloid burden in the stratum lacunosum moleculare (slm). aa. Immunostaining for Aβ (rabbit anti-Aβ 95-2-5) showing whole brain section of ChABC injected APPswe/PS1dE9 mouse hippocampus at low magnification (25x); ab,ab’. Aβ immunostaining of slm on ChABC injected ipsilateral (ab) and contralateral (ab’) sides (100x). ac,ac’. inverted images of (ab and ab’). ad,ad’. PSD-95 staining in the same sections as in (ac,ac’) with slm outlined in blue. ae,ae’. sections from (ac,ac’) thresholded and converted to binary to calculate the area occupied by Aβ. b. Quantitative measurement of area occupied by Aβ in the slm as area occupied by Aβ (left graph; APPswe/PS1dE9 n = 7) and area occupied as per cent of contralateral side (right graph, no ChABC treatment n = 3; ChABC treatment n = 7). Comparison between treatments was made using unpaired Student’s t-test. *p < 0.05 was considered a significant difference between groups
Mentions: In APPswe/PSdE9 mice, 18 days after ChABC injection Aβ burden was measured in the stratum lacunosum moleculare (slm), one region of the hippocampus that contains numerous amyloid plaques. The slm was easily recognized when co-staining the sections for PSDS-95 (Figure 4ad and ad’). The reduction in Aβ plaques was observable in the ChABC-treated hemisphere (eg. Figure 4aa). The per cent of the slm occupied by Aβ after thresholding the immunoreactive density (Figure 4ae) was nearly 50 % lower in ChABC treated slm compared to the non-ChABC treated slm hemisphere (Fig. 4b, left graph; p < 0.05). When the ratio of ipsilateral/contralateral was calculated and compared to vehicle-treated APPswe/PS1dE9 mice, there was approximately a 40 % reduction in Aβ burden. Thus, removal of CS for 18 days after injection of ChABC resulted in a significant reduction in the presence of Aβ in the slm hippocampus in APPswe/PS1dE9 mice.Fig. 4

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