Antibody recognizing 4-sulfated chondroitin sulfate proteoglycans restores memory in tauopathy-induced neurodegeneration

Abstract

Chondroitin sulfate proteoglycans (CSPGs) are the main active component of perineuronal nets (PNNs). Digestion of the glycosaminoglycan chains of CSPGs with chondroitinase ABC or transgenic attenuation of PNNs leads to prolongation of object recognition memory and activation of various forms of plasticity in the adult central nervous system. The inhibitory properties of the CSPGs depend on the pattern of sulfation of their glycosaminoglycans, with chondroitin 4-sulfate (C4S) being the most inhibitory form. In this study, we tested a number of candidates for functional blocking of C4S, leading to selection of an antibody, Cat316, which specifically recognizes C4S and blocks its inhibitory effects on axon growth. It also partly blocks binding of semaphorin 3A to PNNs and attenuates PNN formation. We asked whether injection of Cat316 into the perirhinal cortex would have the same effects on memory as chondroitinase ABC treatment. We found that masking C4S with the Cat316 antibody extended long-term object recognition memory in normal wild-type mice to 24 hours, similarly to chondroitinase or transgenic PNN attenuation. We then tested Cat316 for restoration of memory in a neurodegeneration model. Mice expressing tau with the P301S mutation showed profound loss of object recognition memory at 4 months of age. Injection of Cat316 into the perirhinal cortex normalized object recognition at 3 hours in P301S mice. These data indicate that Cat316 binding to C4S in the extracellular matrix can restore plasticity and memory in the same way as chondroitinase ABC digestion. Our results suggest that antibodies to C4S could be a useful therapeutic to restore memory function in neurodegenerative disorders.

Circadian Rhythms of Perineuronal Net Composition

“…It is important to emphasize that growing and compelling evidence shows that PNN and ECM functions are dictated by dynamic posttranslational modifications of their components mediated by matrix proteases Lasek et al, 2018;Wen et al, 2018). Notably, these modifications determine whether effects of ECM components on synaptic plasticity are inhibitory or permissive (Miyata et al, 2012;Foscarin et al, 2017;Yang et al, 2017). Our data showing cathepsin-S rhythms antiphase to PNN rhythms, and the ability of cathepsin-S to eliminate WFA+ PNN labeling, support this interpretation and represent the first step in examining this process.…”

Muscarinic Receptor-Dependent Long Term Depression in the Perirhinal Cortex and Recognition Memory are Impaired in the rTg4510 Mouse Model of Tauopathy

“…Object recognition studies performed within a Y shaped arena using both homozygous and heterozygous P301S mice (both of which develop a more widespread tau pathology than rTg4510 mice) have also identified deficits at long inter-trial intervals (3 and 24 h) but not at 1 min. These deficits were also shown to be absent in younger pre-symptomatic P301S animals—although the age lacking an effect in the heterozygotes varied between the two studies [28, 29]. This group have also produced deficits in their version of task using viral expression of P301S tau locally in the perirhinal cortex and can afford a degree of phenotypic rescue by manipulating the perineuronal extracellular matrix [28, 29].…”

“…In the former model basal synaptic transmission was depressed but perirhinal LTD appeared normal. Interestingly, these workers find the effects of tauopathy on recognition memory and synaptic transmission can be rescued by manipulation of the perineuronal net [28, 29]. In this study we have examined novel object discrimination in male 8–9 month old rTg4510 mice a widely studied model in which the human disease-associated P301L tau species is overexpressed selectively in the mouse forebrain.…”

Restoring the pattern of proteoglycan sulphation in perineuronal nets corrects age-related memory loss

“…Digestion of inhibitory CSPGs (the main effectors of PNNs) with chondroitinase ABC (ChABC), enables increased formation of inhibitory synapses on PV + neurons (2,9), and enhances memory formation and duration in young animals, as does transgenic attenuation of PNNs (10,11). Moreover in animals with defective memory due to pathology from mutant tau or amyloid-beta, CSPG digestion or antibody treatment to block inhibitory 4-sulphated CS-GAGs restores memory to normal levels (12)(13)(14). Together these previous results demonstrate a role for PNNs in memory, and show that PNN CS-GAGs are the key component (15).…”