Understanding reactive astrogliosis in degenerative proteinopathies through the lens of postmortem brain imaging techniques. (20th December 2022)

• Record Type: Journal Article
• Authors: Kumar, Amit; Fontana, Igor C.; Nordberg, Agneta K
• Is Part Of: Alzheimer's & dementia. Volume 18(2022)Supplement 6
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-12-20
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.065709
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: The discovery and validation of biomarkers beyond amyloid‐β and tau is now considered as a research priority in the Alzheimer's disease (AD) field. In this context, astrocytes ' key homeostatic cells ' in the central nervous system (CNS) are potential targets thanks to their swift response in AD pathology. Astrocytes tend to changes in brain physiology after CNS injury/insults via a specific defence response called reactive astrogliosis. The role of astrocytes in AD pathology is still under examination, however recent studies have openly suggested that reactive astrogliosis is an early event which may precede other hallmarks of the disease. In our recent work, we have speculated, based on clinical/translational in vivo and in vitro brain imaging studies, that there are two waves, ' first (early) and second (late) ', of reactive astrogliosis in AD pathology with a distinct, close‐knit relationship with other pathological markers. Reactive astrogliosis also seems to play a critical role in other proteinopathies, such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). The PET imaging field is advancing very fast and different astrocytic‐tracers are now available, such as 11 C‐Deprenyl (DED) and SMBT‐1 (both targeting MAO‐B) as well as 11 C‐BU99008 (detect imidazoline2 binding sites), which we believe is of utmost relevance to shed more light on the role of reactive astrogliosis, including astrocytic heterogeneity and improve our understanding of the underlying mechanism in these proteinopathies. Method: We used a mixed battery of specialized in vitro radioligand binding assays (saturation and competition studies in brain tissues) and large frozen human brain section autoradiography in AD, PSP, CBD and control brains. Result: In our studies, we demonstrated that BU99008 could visualize reactive astrogliosis and target multiple binding sites in AD brain. We observed that BU99008 and DED varied in their binding behavior in AD and control brains, suggesting that they might be targeting a specific state/or a different sub‐population of astrocytes. Conclusion: Postmortem brain imaging techniques are valuable tools for validation (pre‐clinical) of novel PET‐tracers. Our ongoing studies in PSP and CBD brains as well as with SMBT‐1 will provide deeper insight into the role of reactive astrogliosis in these deadly diseases.