Increased Hyaluronan and TSG-6 in Association with Neuropathologic Changes of Alzheimer’s Disease

Abstract

Little is known about the extracellular matrix (ECM) during progression of AD pathology. Brain ECM is abundant in hyaluronan (HA), a non-sulfated glycosaminoglycan synthesized by HA synthases (HAS) 1–3 in a high molecular weight (MW) form that is degraded into lower MW fragments. We hypothesized that pathologic severity of AD is associated with increases in HA and HA-associated ECM molecules. To test this hypothesis, we assessed HA accumulation and size; HA synthases (HAS) 1–3; and the HA-stabilizing hyaladherin, TSG-6 in parietal cortex samples from autopsied research subjects with not AD (CERAD = 0, Braak = 0–II, n = 12–21), intermediate AD (CERAD = 2, Braak = III–IV, n = 13–18) and high AD (CERAD = 3, Braak = V–VI, n = 32–40) neuropathologic change. By histochemistry, HA was associated with deposits of amyloid and tau, and was also found diffusely in brain parenchyma, with overall HA quantity (measured by ELSA) significantly greater in brains with high AD neuropathology. Mean HA MW was similar among the samples. HAS2 and TSG-6 mRNA expression, and TSG-6 protein levels were significantly increased in high AD and both molecules were present in vasculature, NeuN-positive neurons, and Iba1-positive microglia. These results did not change when accounting for gender, advanced age (≥90 years vs. <90 years), or the clinical diagnosis of dementia. Collectively, our results indicate a positive correlation between HA accumulation and AD neuropathology, and suggest a possible role for HA synthesis and metabolism in AD progression.

The microvascular extracellular matrix in brains with Alzheimer’s disease neuropathologic change (ADNC) and cerebral amyloid angiopathy (CAA)

“…5b) and HA ( Fig. 5c) levels were both significantly higher in modsevere CAA brains (n = 8 for western blot and n = 26 for HA ELISA) vs no CAA brains (n = 4 for western blot and n = 14 for HA ELISA), which was similar to what we have previously found in high ADNC vs not ADNC [31].…”

“…In this context, TSG-6 likely organizes HA molecules into a crosslinked network and plays a protective role in response to brain injury/inflammation [27,29,30]. Our previous studies have found greater amounts of HA and TSG-6 in brains with high ADNC relative to those with no ADNC [31].…”

Hyaluronan regulates synapse formation and function in developing neural networks

“…In particular, HA removal was sufficient to drive a hyperexcitable state, which is characteristic of neurodevelopmental disorders, including epilepsy, intellectual disability, and autism spectrum disorders 12,35,40 . Conversely, our observation that HA decreases excitatory synapse formation could have implications for aging and Alzheimer's Disease, both of which exhibit HA accumulation and synapse loss [69][70][71][72] . In particular, aging is associated with loss of synapses that form on highly plastic thin spines 69 , which resemble the filopodia-like spine precursors involved in prenatal synaptogenesis 30,48,73 .…”

The extracellular matrix of the blood–brain barrier: structural and functional roles in health, aging, and Alzheimer’s disease

“…TSG6 mRNA and protein were also significantly increased in AD brains. 80 It is generally accepted that CSPG accumulation is increased during neurodegeneration. 59 Similar to what has been reported during CNS scar formation, the characteristic lesions of Abeta and neurofibrillary tangles NFT are surrounded by reactive gliosis as measured by GFAP positive astrocytes.…”