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

Aarun S Hendrickson; Kendra L Francis; Asmit Kumar; Jaden P Le; Jarrad M Scarlett; C Dirk Keene; David A Tovar; Kimberly M Alonge

doi:10.3389/fnins.2024.1396101

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

Front Neurosci. 2024 Apr 30:18:1396101. doi: 10.3389/fnins.2024.1396101. eCollection 2024.

Authors

Aarun S Hendrickson^{1

2}, Kendra L Francis^{2

3}, Asmit Kumar^{1

2}, Jaden P Le^{1

2}, Jarrad M Scarlett^{2

3}, C Dirk Keene⁴, David A Tovar⁵, Kimberly M Alonge^{1

2}

Affiliations

¹ Medicinal Chemistry, University of Washington, Seattle, WA, United States.
² Department of Medicine, University of Washington Medicine Diabetes Institute, Seattle, WA, United States.
³ Department of Pediatric Gastroenterology and Hepatology, Seattle Children's Hospital, Seattle, WA, United States.
⁴ Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, United States.
⁵ Department of Psychology, Vanderbilt University, Nashville, TN, United States.

Abstract

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.

Keywords: Alzheimer’s disease; chondroitin sulfate; glycosmainoglycans; mass spectrometry; perineuronal nets; proteoglycans; translation.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by the National Institute on Aging (NIH-NIA) grants P30 AG066509 (KA) and R21 AG074152 (KA). Additional funding includes the National Institute of Allergy and Infectious Diseases (NIAID) grant DP2 AI171150 (KA) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIH-NIDDK) grants K08 DK114474 (JS), R03 DK128383 (JS), and F32 DK131695 (KF). In addition, support was utilized from the Department of Defense (DoD) grants AZ210089 (KA) and W81XWH2110635 (JS). Mass spectrometry work was supported by University of Washington School of Pharmacy’s Mass Spectrometry Center. Research brain donor tissues are provided by the UW BioRepository and Integrated Neuropathology (BRaIN) laboratory, which is supported in part by the UW ADRC (P30 AG066509), the Kaiser Permanente Washington Adult Changes in Thought (ACT) study (U19 AG066567), and the Nancy and Buster Alvord Endowment (CK). Funding was also provided by the Vanderbilt Kennedy Center IDD-Reads grant (DT).