Assessing translational applicability of perineuronal net dysfunction in Alzheimer's disease across species.

In the context of aging and age-associated neurodegenerative disorders, the brain's extracellular matrix (ECM) serves as a critical regulator for neuronal health and cognitive function. Within the extracellular space, proteoglycans and their glycosaminoglycan attachments play essential roles in forming, stabilizing, and protecting neural circuits throughout neurodevelopment and adulthood. Recent studies in rodents reveal that chondroitin sulfate-glycosaminoglycan (CS-GAG) containing perineuronal nets (PNNs) exhibit both structural and compositional differences throughout the brain. While animal studies are illuminating, additional research is required to translate these interregional PNN/CS-GAG variations to human brain tissue. In this perspective article, we first investigate the translational potential for interregional CS-GAG variances across species as novel targets for region-specific therapeutic development. We specifically focus on the observation that alterations in brain PNN-associated CS-GAGs have been linked with the progression of Alzheimer's disease (AD) neuropathology in humans, but these changes have not been fully recapitulated in rodent models of this disease. A second highlight of this perspective article investigates whether AD-associated shifts in CS-GAGs in humans may be dependent on region-specific baseline differences in CS-GAG sulfation patterning. The current findings begin to disentangle the intricate relationships between the interregional differences in brain PNN/CS-GAG matrices across species, while emphasizing the need to better understand the close relationship between dementia and changes in brain CS-GAG sulfation patterns in patients with AD and related dementias.

Perineuronal net deglycosylation associates with tauopathy-induced gliosis and neurodegeneration.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by clinical symptoms of memory and cognitive deficiencies. Postmortem evaluation of AD brain tissue shows proteinopathy that closely associate with the progression of this dementing disorder, including the accumulation of extracellular beta amyloid (Aß) and intracellular hyperphosphorylated tau (pTau) with neurofibrillary tangles (NFTs). Current therapies targeting Aß have limited clinical efficacy and life-threatening side effects and highlight the need for alternative treatments targeting pTau and other pathophysiologic mechanisms driving AD pathogenesis. The brain's extracellular matrices (ECM), particularly perineuronal nets (PNNs), play a crucial role in brain functioning and neurocircuit stability, and reorganization of these unique PNN matrices has been associated with the progression of AD and accumulation of pTau in humans. We hypothesize that AD-associated changes in PNNs may in part be driven by the accumulation of pTau within the brain. In this work, we investigated whether the presence of pTau influenced PNN structural integrity and PNN chondroitin sulfate-glycosaminoglycan (CS-GAG) compositional changes in two transgenic mouse models expressing tauopathy-related AD pathology, PS19 (P301S) and Tau4RTg2652 mice. We show that PS19 mice exhibit an age-dependent loss of hippocampal PNN CS-GAGs, but not the underlying aggrecan core protein structures, in association with pTau accumulation, gliosis, and neurodegeneration. The loss of PNN CS-GAGs were linked to shifts in CS-GAG sulfation patterns to favor the neuroregenerative isomer, 2S6S-CS. Conversely, Tau4RTg2652 mice exhibit stable PNN structures and normal CS-GAG isomer composition despite robust pTau accumulation, suggesting a critical interaction between neuronal PNN glycan integrity and neighboring glial cell activation. Overall, our findings provide insights into the complex relationship between PNN CS-GAGs, pTau pathology, gliosis, and neurodegeneration in mouse models of tauopathy, and offer new therapeutic insights and targets for AD treatment.