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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

Intracerebral ChABC injection results in a marked and long-lasting decline in CS-bearing PGs. Low magnification micrographs (25x) of Wisteria floribunda agglutinin (WFA) staining 1, 2, and 3 weeks after ChABC injection (5 mU/1 μL). Arrowhead represents injection site for ChABC. Note the widespread loss of WFA immunoreactivity in the injected (left side) cortex and hippocampus (area with white outline). Injection target was to the ventral side of the corpus callosum on the dorsal side of dorsal hippocampus
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Fig3: Intracerebral ChABC injection results in a marked and long-lasting decline in CS-bearing PGs. Low magnification micrographs (25x) of Wisteria floribunda agglutinin (WFA) staining 1, 2, and 3 weeks after ChABC injection (5 mU/1 μL). Arrowhead represents injection site for ChABC. Note the widespread loss of WFA immunoreactivity in the injected (left side) cortex and hippocampus (area with white outline). Injection target was to the ventral side of the corpus callosum on the dorsal side of dorsal hippocampus

Mentions: Mouse protocols used in these experiments were approved by the Institute for Animal Care and Use Committee at the University of Arkansas for Medical Sciences and effort was made to limit the number of animals required in each experiment and any pain produced by the surgery. B6C3-Tg(APPswe,PSEN1dE9)85Dbo mice (APPswe/PS1dE9) were purchased from Jackson Laboratory (Bar Harbor, MN) and a live colony was maintained in our local vivarium by mating hemizygotes with nontransgenic animals. Litters from these matings were used for both non-transgenic controls and APPswe/PS1dE9 mice. Mice were aged to 14 months and then underwent surgery for brain injection of chondroitinase ABC (ChABC; Sigma Aldrich, St. Louis, MO). Mice were anesthetized with inhaled isoflurane and mounted on a Kopf stereotaxic apparatus (Tujunga, CA) with a specialized nose cone to accommodate brain surgery. The body was placed on a heating pad, the head sterilized and shaved, an incision made at the sagittal midline, and a hole was made in the skull using a high speed drill. A 1 μl injection of either ChABC (5 mU/μl), diluted in saline containing 0.1 % BSA, or saline with 0.1 % BSA was made using a 10 μl Hamilton syringe with a 32 gauge blunt end needle to the following site at the right dorsal hippocampus (distance in mm from bregma: posterior 1.8 mm, lateral 1.2 mm, ventral 1.2 mm). The injection was made over a two minute span and after the completion of the injection the needle was held in place for an additional two minutes. The needle was then removed, the hole closed with bone wax, the incision sutured, and the animal returned to a cage containing a heating pad for 30 min and then back to the regular cage. Eighteen days after surgery, mice were euthanized with pentobarbital and cardiac-aorta perfused with ice cold saline followed by 4 % paraformaldehyde. The brain was dissected and fixed overnight at 4 C in 4 % paraformaldehyde (Sigma-Aldrich). Prior to cryostat sectioning, the brains were incubated in 15 % and 30 % sucrose prepared in PBS. For detection of the length of time that ChABC reduces Wisteria floribunda agglutinin (WFA) staining (Fig. 3), four month old C57Bl/6 mice were injected with the same dose of ChABC and euthanized 1, 2 and 3 weeks following surgery, their brain collected and processed for histochemistry as described above. Sections were stained with WFA (Vector Laboratories, Burlingame, CA).


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)

Intracerebral ChABC injection results in a marked and long-lasting decline in CS-bearing PGs. Low magnification micrographs (25x) of Wisteria floribunda agglutinin (WFA) staining 1, 2, and 3 weeks after ChABC injection (5 mU/1 μL). Arrowhead represents injection site for ChABC. Note the widespread loss of WFA immunoreactivity in the injected (left side) cortex and hippocampus (area with white outline). Injection target was to the ventral side of the corpus callosum on the dorsal side of dorsal hippocampus
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Fig3: Intracerebral ChABC injection results in a marked and long-lasting decline in CS-bearing PGs. Low magnification micrographs (25x) of Wisteria floribunda agglutinin (WFA) staining 1, 2, and 3 weeks after ChABC injection (5 mU/1 μL). Arrowhead represents injection site for ChABC. Note the widespread loss of WFA immunoreactivity in the injected (left side) cortex and hippocampus (area with white outline). Injection target was to the ventral side of the corpus callosum on the dorsal side of dorsal hippocampus
Mentions: Mouse protocols used in these experiments were approved by the Institute for Animal Care and Use Committee at the University of Arkansas for Medical Sciences and effort was made to limit the number of animals required in each experiment and any pain produced by the surgery. B6C3-Tg(APPswe,PSEN1dE9)85Dbo mice (APPswe/PS1dE9) were purchased from Jackson Laboratory (Bar Harbor, MN) and a live colony was maintained in our local vivarium by mating hemizygotes with nontransgenic animals. Litters from these matings were used for both non-transgenic controls and APPswe/PS1dE9 mice. Mice were aged to 14 months and then underwent surgery for brain injection of chondroitinase ABC (ChABC; Sigma Aldrich, St. Louis, MO). Mice were anesthetized with inhaled isoflurane and mounted on a Kopf stereotaxic apparatus (Tujunga, CA) with a specialized nose cone to accommodate brain surgery. The body was placed on a heating pad, the head sterilized and shaved, an incision made at the sagittal midline, and a hole was made in the skull using a high speed drill. A 1 μl injection of either ChABC (5 mU/μl), diluted in saline containing 0.1 % BSA, or saline with 0.1 % BSA was made using a 10 μl Hamilton syringe with a 32 gauge blunt end needle to the following site at the right dorsal hippocampus (distance in mm from bregma: posterior 1.8 mm, lateral 1.2 mm, ventral 1.2 mm). The injection was made over a two minute span and after the completion of the injection the needle was held in place for an additional two minutes. The needle was then removed, the hole closed with bone wax, the incision sutured, and the animal returned to a cage containing a heating pad for 30 min and then back to the regular cage. Eighteen days after surgery, mice were euthanized with pentobarbital and cardiac-aorta perfused with ice cold saline followed by 4 % paraformaldehyde. The brain was dissected and fixed overnight at 4 C in 4 % paraformaldehyde (Sigma-Aldrich). Prior to cryostat sectioning, the brains were incubated in 15 % and 30 % sucrose prepared in PBS. For detection of the length of time that ChABC reduces Wisteria floribunda agglutinin (WFA) staining (Fig. 3), four month old C57Bl/6 mice were injected with the same dose of ChABC and euthanized 1, 2 and 3 weeks following surgery, their brain collected and processed for histochemistry as described above. Sections were stained with WFA (Vector Laboratories, Burlingame, CA).

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