The “Loss” of Perineuronal Nets in Alzheimer's Disease: Missing or Hiding in Plain Sight?

Abstract

Perineuronal nets (PNNs) are chondroitin-sulfate glycosaminoglycan (CS-GAG) containing extracellular matrix structures that assemble around neurons involved in learning, memory, and cognition. Owing to the unique patterning of negative charges stemming from sulfate modifications to the attached CS-GAGs, these matrices play key roles in mediating glycan-protein binding, signaling interactions, and charged ion buffering of the underlying circuitry. Histochemical loss of PNN matrices has been reported for a range of neurocognitive and neurodegenerative diseases, implying that PNNs might be a key player in the pathogenesis of neurological disorders. In this hypothesis and theory article, we begin by highlighting PNN changes observed in human postmortem brain tissue associated with Alzheimer's disease (AD) and corresponding changes reported in rodent models of AD neuropathology. We then discuss the technical limitations surrounding traditional methods for PNN analyses and propose alternative explanations to these historical findings. Lastly, we embark on a global re-evaluation of the interpretations for PNN changes across brain regions, across species, and in relation to other neurocognitive disorders.

CCR5 deficiency normalizes TIMP levels, working memory, and gamma oscillation power in APOE4 targeted replacement mice

“…Future studies are thus warranted to assess the downstream mechanisms by which CCR5 normalizes gamma power and cognitive endpoints in the APOE4 TR mice. Potential approaches include interventions that specifically target the ECM (Dubisova et al ., 2022), and examination of ECM proteins in fixed brain tissue from individuals with and without APOE4 with care to account for potential differences in glycan sulfation (Logsdon et al ., 2022; Scarlett et al ., 2022). In addition, since APOE4 may increase the risk of recurrent episodes of major depression, a disorder often associated with reduced gamma power and cognitive deficits (Khalid et al ., 2016; Papp et al ., 2018; Alaiyed et al ., 2019), future studies may be warranted to test CCR5 antagonists for this disorder.…”

HS, an Ancient Molecular Recognition and Information Storage Glycosaminoglycan, Equips HS-Proteoglycans with Diverse Matrix and Cell-Interactive Properties Operative in Tissue Development and Tissue Function in Health and Disease

“…Recently, attention has also focused on the role of PNNs in the control of neuronal and synaptic plasticity in health and disease [ 359 , 360 ], it is now clear that PNNs also have important roles to play in cognitive learning processes and the modulation of memory. Disruption in PNNs has been observed in AD [ 361 , 362 , 363 , 364 ] and with increased levels of Tau pathology in neurodegenerative conditions [ 365 ]. HS-PGs also have roles in the deposition of pathological protein aggregates in brain tissues [ 317 ].…”

Extracellular matrix and synapse formation

“…In addition, overstabilized PNN inhibits the growth of neurites and restricts the signaling transmission between neurons and synaptic plasticity [ 173 , 174 ]. Other work has reported the remodeling of PNN glycan structures in AD [ 175 ]. The chondroitin-sulfate glycosaminoglycan (CS-GAG), which is attached to the CSPG proteins in PNN, illustrates sulfation modifications in AD and results in the remodeling of PNN [ 175 ].…”

“…Other work has reported the remodeling of PNN glycan structures in AD [ 175 ]. The chondroitin-sulfate glycosaminoglycan (CS-GAG), which is attached to the CSPG proteins in PNN, illustrates sulfation modifications in AD and results in the remodeling of PNN [ 175 ]. The treatment of AD model mice with ChABC reduces Aβ plaques' deposition, restores synaptic density, and alleviates AD symptoms, such as LTP impairment and hippocampus-dependent memory loss [ 176 ].…”