The extracellular matrix (ECM) and neuroinflammation are increasingly implicated in the pathogenesis of neurodegenerative diseases, such as Alzheimer's Disease (AD). Hyaluronan (HA), a modulator of inflammation, is a non-sulfated glycosaminoglycan comprised of repeating disaccharides that is the major ECM component of the brain microvasculature and brain parenchyma. AD neuropathology is characterized by plaques, tangles and a disordered microvasculature, but little is known about the relationship between HA and the microvascular and neuropathologic findings of AD. Studies indicate that HA accumulation increases in the spinal fluid in AD and is altered in regions of AD plaques, but the direction and magnitude are confounded by lack of specific HA markers, gender differences and the presence of concurrent macrovascular pathology. HA is a ubiquitous component of brain parenchyma that is accessible and modifiable. HA is newly synthesized by membrane-bound HA synthases (HASes 1-3) in a high MW form (e.g., 1000kDa) that is constantly degraded by hyaluronidases (HYALs, primarily isoforms 1-3.) HA has size-dependent effects on cell behavior with low MW HA (e.g., 50kDA) forms that are neuroinflammatory, both directly and through HA stimulation of cytokine release. Inflammation, in turn, is a major driver of neurodegeneration. As such, HA could contribute to the inflammatory environment in AD. A better understanding of the association of HA with the microvasculature and neuropathology of AD is necessary in order to determine if the ECM, and HA specifically, is a logical therapeutic target in AD. The hypothesis: HA is a driver of inflammation in neurodegenerative diseases, such that HA levels associate with increased AD microvascular pathology and neuropathology. A well-characterized repository of frontal cortex tissues from subjects aged 70-101 years (mean 85), previously examined for quantitative A and tau and amyloid angiopathy, will be utilized. Sections will have no vascular infarcts. All subjects have had the presence or absence of clinical dementia determined antemortem. By study end, nearly 200 samples with ?no? (Cerad=0; Braak=0-2), ?moderate? (Cerad=2; Braak=3-4) or ?severe? AD neuropath (Cerad=3; Braak 5-6) will be examined in 3 aims: 1) determine the association between neuropathology of AD, neuroinflammation and HA accumulation; 2) examine the capillary microvasculature (vessel density, proliferation and tight junction proteins) in AD neuropathology and its relationship to HA accumulation (reflecting synthesis and degradation); and 3) define the spatial relationship between HA accumulation and amyloid angiopathy, a separate but related pathology, in the brain microvasculature. Whether HA impacts concordance between pathology and the clinical diagnosis of dementia will also be established. This study focuses on an understudied area and is significant - analyzing histologic features is fundamental to understanding the potential role of HA in AD pathogenesis, and to determine if HA is a logical therapeutic target in AD.
The extracellular matrix (ECM) and neuroinflammation are increasingly implicated in the pathogenesis of Alzheimer's Disease (AD). Hyaluronan (HA), the dominant extracellular matrix component in the brain vasculature and parenchyma, is the source of neuroinflammatory low MW (LMW) HA that promotes neurodegeneration. This application will establish the association between AD neuropathology, the capillary microvascular changes of AD, amyloid angiopathy, and HA accumulation in frontal cortex specimens from a well-characterized repository of human brain samples.
| Reed, May J; Damodarasamy, Mamatha; Pathan, Jasmine L et al. (2018) The Effects of Normal Aging on Regional Accumulation of Hyaluronan and Chondroitin Sulfate Proteoglycans in the Mouse Brain. J Histochem Cytochem 66:697-707 |
| Reed, May J; Damodarasamy, Mamatha; Pathan, Jasmine L et al. (2018) Increased Hyaluronan and TSG-6 in Association with Neuropathologic Changes of Alzheimer's Disease. J Alzheimers Dis : |
