Arachnoid Granulation Senescence in Aging, CAA and Alzheimer's Disease

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PROJECT SUMMARY/ABSTRACT Arachnoid granulations (AG) are a unique tissue composite within the mammalian nervous system and are known to enlarge with aging. Accumulating evidence suggest that AGs subserve specialized roles in glymphatic- lymphatic drainage and may be a critical factor in brain resilience and diseases, including Alzheimer’s disease. In spite of this, these meningeal structures have been poorly investigated across species. Historically, AGs have been perceived to play a passive role in intracranial cerebrospinal fluid transport. Substantial gaps in knowledge remain regarding their cell constituents and arrangement, and their associations with disease, due in large part to lack of systematic and high-resolution microscopic analyses. To advance the field, better characterization of AG structure is needed. In this study, we will use high-resolution microscopy techniques to elucidate the structure of human AG and their morphological and compositional changes with aging. Their anatomy will be mapped using immunohistochemical techniques and their features will be correlated with established neuropathological and neurological measures of disease. For this work, we will leverage a rich resource of clinical and pathologic material available from the Rush Religious Orders Study and Memory and Aging Project (ROSMAP) and will collect and analyze novel data pertaining to the unique structure of AG. The hypothesis is that AGs function as a critical neuroimmune tissue and that their senescence is associated with Alzheimer’s disease (AD). In Aim 1, we will examine the associations of AG senescence with intracranial beta-amyloid (βA) accumulation and pathology of AD. In Aim 2, we will examine the associations of AG senescence with clinically defined AD dementia. In Aim 3, we will explore the role of apolipoprotein E genotype on the associations between AG senescent features with intracranial βA load and cognition. In each aim, we will investigate how relationships differ by age, clinical or pathological AD stage, sex, and comorbid diseases. Overall, these studies have the potential to uncover new knowledge regarding the AG milieu in aging and AD as well as novel insights into the person-specific nature of the glymphatic-lymphatic connection. The proposed investigations will advance the field and may reveal mechanistic, diagnostic and prognostic factors for AD while laying a framework for studying AGs in the setting of other age-related neurological diseases.