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

Matthew D Howell,Brenda M Gannon,Paul E Gottschall,Michael A Cozart,Lauren A Bailey

doi:10.1186/s40478-015-0233-z

Matthew D Howell, Brenda M Gannon + Show 3 more

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https://doi.org/10.1186/s40478-015-0233-z

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Abstract

IntroductionSubstantial 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.ResultsIn 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.ConclusionsIt 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-015-0233-z) contains supplementary material, which is available to authorized users.

Highlights

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
It is possible that lecticans, brevican, inhibit synaptic plasticity in this model of Alzheimer’s disease (AD)
We demonstrated that Aβ binds to brain-derived lecticans, Fig. 5 chondroitinase ABC (ChABC) injection increases density of synaptophysin surrounding Aβ plaques in the slm. aa. freehand rings were drawn around three regions of an amyloid plaque. 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

Summary

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. Numerous molecular events occur in the post-synaptic density of an excitatory synapse in response to a train of pre-synaptic action potentials These include a change in transmission sensitivity and alterations in the structure of the dendritic spine, and these interrelated functions are essential for the formation and other aspects of memory [1,2,3]. ChABC treatment results in removal of CS chains from lectican core proteins (and other CS-bearing PGs) These studies demonstrated that removal of CS chains stimulated plasticity as measured by functional outcomes including visual ocular dominance [7, 8], fear memory [9] and other forms of learning [10]. These findings suggest that the ECM lattice present at the synapse could be a therapeutic target for neurological disorders with diminished synaptic plasticity

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