Limits...
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

Binding of Aβ isoforms to DEAE purified molecules including brevican. a. Western blot of Aβ isoforms used in binding assay to DEAE products in “b”. b. Solid phase, dose-dependent, binding of Aβ1-42 isoforms (monomeric, oligomeric and fibrillar) and Aβ(1–16) to DEAE purified molecules. The mean EC50s (n = 5 binding assays) for multiple conformational Aβ binding to DEAE purified brain protein was evaluated using one way ANOVA followed by Tukey’s multiple comparison test. EC50 for monomeric, oligomeric and fibrillar Aβ1-42 is significantly lower compared to the EC50 for Aβ1-16; (p < 0.05). c. Immunoprecipitation of brevican with mouse anti-Aβ 4G8 after soluble binding to DEAE product. Western blot was performed with mouse anti-brevican antibody. Lane identities: lane 1 DEAE extract only; lane 2 fibrillar Aβ only; lane 3 4G8 antibody only; lane 4 DEAE extract + monomeric Aβ; lane 5 DEAE extract + oligomeric Aβ; lane 6 DEAE extract + fibrillar Aβ. Anti-Aβ 4G8 pulled down brevican bound to oligomeric (lane 5) and fibrillar Aβ (lane 6). Lower molecular weight bands correspond to heavy and light IgG chains. Although all three isoforms of Aβ1-42 bound to brevican, binding to monomeric Aβ was markedly lower than binding to oligomeric and fibrillar Aβ
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig2: Binding of Aβ isoforms to DEAE purified molecules including brevican. a. Western blot of Aβ isoforms used in binding assay to DEAE products in “b”. b. Solid phase, dose-dependent, binding of Aβ1-42 isoforms (monomeric, oligomeric and fibrillar) and Aβ(1–16) to DEAE purified molecules. The mean EC50s (n = 5 binding assays) for multiple conformational Aβ binding to DEAE purified brain protein was evaluated using one way ANOVA followed by Tukey’s multiple comparison test. EC50 for monomeric, oligomeric and fibrillar Aβ1-42 is significantly lower compared to the EC50 for Aβ1-16; (p < 0.05). c. Immunoprecipitation of brevican with mouse anti-Aβ 4G8 after soluble binding to DEAE product. Western blot was performed with mouse anti-brevican antibody. Lane identities: lane 1 DEAE extract only; lane 2 fibrillar Aβ only; lane 3 4G8 antibody only; lane 4 DEAE extract + monomeric Aβ; lane 5 DEAE extract + oligomeric Aβ; lane 6 DEAE extract + fibrillar Aβ. Anti-Aβ 4G8 pulled down brevican bound to oligomeric (lane 5) and fibrillar Aβ (lane 6). Lower molecular weight bands correspond to heavy and light IgG chains. Although all three isoforms of Aβ1-42 bound to brevican, binding to monomeric Aβ was markedly lower than binding to oligomeric and fibrillar Aβ

Mentions: Previous data has also shown that CS-bearing PGs bind to Aβ, but it is not known whether Aβ binds to brain-derived lecticans [10, 30]. Binding of Aβ to lecticans may enhance the inhibition of synaptic plasticity. Thus, an extract enriched with CS-bearing PGs was purified from whole mouse brain and this extract was used to perform a solid-phase binding assay with various forms of Aβ (Fig. 2a and b). We observed a dose-dependent increase in monomeric, oligomeric, and fibrillar Aβ1-42 binding to the DEAE extract (Fig. 2b). The EC50 for monomeric was 1.6 ± 0.12 μM, oligomeric was 2.4 ± 0.2 μM, and fibrillar was 2.7 ± 0.3 μM for variants of Aβ1-42 and 50.0 ± 3.0 μM for Aβ1-16. All three conformations of Aβ1-42 showed significantly higher affinity binding to CS-bearing PGs compared to Aβ1-16 (n = 5 assays; p < 0.05). Interestingly, when conducting soluble binding of various forms of Aβ1-42 with DEAE extract, immunoprecipitating with anti-Aβ antibody and probing for brevican on a Western blot, oligomeric and fibrillar Aβ showed greater binding to brevican compared to monomeric Aβ1-42 (Fig. 2c), although there was binding by all three forms.Fig. 2


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)

Binding of Aβ isoforms to DEAE purified molecules including brevican. a. Western blot of Aβ isoforms used in binding assay to DEAE products in “b”. b. Solid phase, dose-dependent, binding of Aβ1-42 isoforms (monomeric, oligomeric and fibrillar) and Aβ(1–16) to DEAE purified molecules. The mean EC50s (n = 5 binding assays) for multiple conformational Aβ binding to DEAE purified brain protein was evaluated using one way ANOVA followed by Tukey’s multiple comparison test. EC50 for monomeric, oligomeric and fibrillar Aβ1-42 is significantly lower compared to the EC50 for Aβ1-16; (p < 0.05). c. Immunoprecipitation of brevican with mouse anti-Aβ 4G8 after soluble binding to DEAE product. Western blot was performed with mouse anti-brevican antibody. Lane identities: lane 1 DEAE extract only; lane 2 fibrillar Aβ only; lane 3 4G8 antibody only; lane 4 DEAE extract + monomeric Aβ; lane 5 DEAE extract + oligomeric Aβ; lane 6 DEAE extract + fibrillar Aβ. Anti-Aβ 4G8 pulled down brevican bound to oligomeric (lane 5) and fibrillar Aβ (lane 6). Lower molecular weight bands correspond to heavy and light IgG chains. Although all three isoforms of Aβ1-42 bound to brevican, binding to monomeric Aβ was markedly lower than binding to oligomeric and fibrillar Aβ
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig2: Binding of Aβ isoforms to DEAE purified molecules including brevican. a. Western blot of Aβ isoforms used in binding assay to DEAE products in “b”. b. Solid phase, dose-dependent, binding of Aβ1-42 isoforms (monomeric, oligomeric and fibrillar) and Aβ(1–16) to DEAE purified molecules. The mean EC50s (n = 5 binding assays) for multiple conformational Aβ binding to DEAE purified brain protein was evaluated using one way ANOVA followed by Tukey’s multiple comparison test. EC50 for monomeric, oligomeric and fibrillar Aβ1-42 is significantly lower compared to the EC50 for Aβ1-16; (p < 0.05). c. Immunoprecipitation of brevican with mouse anti-Aβ 4G8 after soluble binding to DEAE product. Western blot was performed with mouse anti-brevican antibody. Lane identities: lane 1 DEAE extract only; lane 2 fibrillar Aβ only; lane 3 4G8 antibody only; lane 4 DEAE extract + monomeric Aβ; lane 5 DEAE extract + oligomeric Aβ; lane 6 DEAE extract + fibrillar Aβ. Anti-Aβ 4G8 pulled down brevican bound to oligomeric (lane 5) and fibrillar Aβ (lane 6). Lower molecular weight bands correspond to heavy and light IgG chains. Although all three isoforms of Aβ1-42 bound to brevican, binding to monomeric Aβ was markedly lower than binding to oligomeric and fibrillar Aβ
Mentions: Previous data has also shown that CS-bearing PGs bind to Aβ, but it is not known whether Aβ binds to brain-derived lecticans [10, 30]. Binding of Aβ to lecticans may enhance the inhibition of synaptic plasticity. Thus, an extract enriched with CS-bearing PGs was purified from whole mouse brain and this extract was used to perform a solid-phase binding assay with various forms of Aβ (Fig. 2a and b). We observed a dose-dependent increase in monomeric, oligomeric, and fibrillar Aβ1-42 binding to the DEAE extract (Fig. 2b). The EC50 for monomeric was 1.6 ± 0.12 μM, oligomeric was 2.4 ± 0.2 μM, and fibrillar was 2.7 ± 0.3 μM for variants of Aβ1-42 and 50.0 ± 3.0 μM for Aβ1-16. All three conformations of Aβ1-42 showed significantly higher affinity binding to CS-bearing PGs compared to Aβ1-16 (n = 5 assays; p < 0.05). Interestingly, when conducting soluble binding of various forms of Aβ1-42 with DEAE extract, immunoprecipitating with anti-Aβ antibody and probing for brevican on a Western blot, oligomeric and fibrillar Aβ showed greater binding to brevican compared to monomeric Aβ1-42 (Fig. 2c), although there was binding by all three forms.Fig. 2

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