Fig. 6

Proposed model for Lin Body interaction with glia. This figure illustrates our hypothesis for the potential sequala occurring with Lin Bodies and the resulting glial changes observed in and around capillaries throughout the brain. Vascular pathologies, such as arteriolosclerosis, occur in neurodegenerative diseases such as LATE-NC. However, it is now understood that TDP-43 within blood vessels is also associated with vascular changes, including breakdown and increased permeability of the BBB, resulting in TDP-43 leakage (A) and microhemorrhages (B). In response, reactive astrocytes attempt to sequester leaking TDP-43, resulting in localization within the endfeet (C). Following intracerebral hemorrhaging, processes such as erythrophagocytosis lead to increased intracellular levels of iron and iron storage proteins, including ferritin (D). Once internalized, TDP-43 and increased levels of iron lead to astrocyte morphological changes without an apparent increase in the number of cells (E). Typically, cerebral vasculature is covered by astrocytic endfeet, which may represent a first response to leakage of vascular TDP-43. Nonetheless, should astrocytes become incapable of an adequate response, we might observe an accumulation of perivascular Lin bodies not colocalizing with either GFAP or IBA1. (F). Finally, microglia and peripheral macrophages are recruited to restore homeostasis, resulting in an increased population of IBA1⁺ cells surrounding pTDP-43⁺ vessels (G)