Decoding perineuronal net glycan sulfation patterns in the Alzheimer's disease brain

Abstract

The extracellular matrix (ECM) of the brain comprises unique glycan "sulfation codes" that influence neurological function. Perineuronal nets (PNNs) are chondroitin sulfate-glycosaminoglycan (CS-GAG) containing matrices that enmesh neural networks involved in memory and cognition, and loss of PNN matrices is reported in patients with neurocognitive and neuropsychiatric disorders including Alzheimer's disease (AD). Using liquid chromatography tandem mass spectrometry (LC-MS/MS), we show that patients with a clinical diagnosis of AD-related dementia undergo a recoding of their PNN-associated CS-GAGs that correlates to Braak stage progression, hyperphosphorylated tau (p-tau) accumulation, and cognitive impairment. As these CS-GAG sulfation changes are detectable prior to the regional onset of classical AD pathology, they may contribute to the initiation and/or progression of the underlying degenerative processes and implicate the brain matrix sulfation code as a key player in the development of AD clinicopathology.

Changes in Brain Matrix Glycan Sulfation Associate With Reactive Gliosis and Motor Coordination in Mice With Head Trauma

“…CS/DS disaccharides were isolated and quantified according to our previously published methods (Alonge et al, 2019(Alonge et al, , 2020Logsdon et al, 2021). Five PFA-fixed coronal brain sections (30 µm) from each mouse were chosen for CS/DS disaccharide extraction and quantification.…”

“…LC-MS/MS was performed using a Waters Acquity I-class ultraperformance liquid chromatographic system (UPLC) coupled to the same Waters Xevo TQ-S system. Disaccharides were resolved by porous graphitic chromatography (Hypercarb column; 2.1 × 50 mm, 3 µm; ThermoFisher) as described previously (Alonge et al, 2019(Alonge et al, , 2020Logsdon et al, 2021). Assigned MRM channels were: 4S-CS, m/z 458 > 300; 2S4S-DS and 4S6S-CS, m/z 538 > 300; 6S-CS, m/z 458 > 282; 2S6S-CS, m/z 268 > 282; 0S-CS, m/z 378 > 175.…”

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

“…Perineuronal nets (PNNs) were first described by Camillo Golgi over a century ago as “delicate [pericellular] coverings mainly reticular in structure… of a continuous envelope that enwraps the body of all the nerve cells…” (Golgi, 1898 ; Vitellaro-Zuccarello et al, 1998 ). Further investigation showed that these PNN matrices exhibit a honeycomb structured ECM morphology that form condensed pericellular coats enmeshing the soma and proximal dendrites of key neurons in the brain ( Figures 1A,B ; see Alonge et al, 2020 ; Logsdon et al, 2021 ). The lattice-like formation characteristic of PNNs are produced by a combination of link protein (HAPLN) anchorage of PNN-associated chondroitin sulfate proteoglycans (CSPGs) onto the underlying neuron-attached hyaluronan (HA) and hyaluronan synthase (HAS) backbones, which are then molded into a net formation by Tenascin-R (TnR) cross-linkage of the CSPGs ( Figure 1C ).…”

“… Perineuronal net composition and structure. (A) PNNs enmesh the soma and proximal axons and dendrites of target neurons (see Logsdon et al, 2021 ). Synaptic contacts between pre- and post- synaptic neurons are dynamically regulated by gaps formed in the PNN lattice.…”

Revisiting the grammar of Tau aggregation and pathology formation: how new insights from brain pathology are shaping how we study and target Tauopathies

“…GAGs are a large class of long anionic unbranched polysaccharides consisting of repeating disaccharide units. 336 Based on the compositional differences, GAGs comprise five classes of molecules, such as hyaluronic acid, predominantly associated with skin tissues, synovial fluid and articular cartilage; 337 chondroitin sulfate, which is a major component of perineuronal nets, changes in sulfation patterns of which were is linked to cognitive decline in AD, 338 as well as dermatan sulfate, keratan sulfate, and HS, all of which play important structural and signaling roles in neural and other tissues. 336,[339][340][341] Heparan sulfate proteoglycans (HSPGs) have been implicated in Tau pathology formation and spreading at the stages of its release from the affected cell, as well as in facilitating the internalization of pathogenic Tau forms by the neighboring cell (reviewed in ref.…”