Understanding Limbic-Predominant Age-Related TDP-43 Encephalopathy (LATE): The Intersection of Pathology and Immune Dysregulation ^†

Introduction: In the present state, a novel amnesic and AD-like dementia pathology emerges in the ageing brains, namely Limbic-predominant age-related TDP-43 encephalopathy (LATE). The disease is represented by aberrant splitting, clumping, phosphorylation, and massive accumulations of TDP-43 within the cytoplasm of cells involving neurons and glia. The abnormal regulation of TDP-43 is responsible for the mediated alteration of signaling events, such as deprived synaptic transmission, progressive neuronal degeneration, and motor deviations. Therefore, TDP-43 is a central player for LATE-associated CNS pathologies.

Material and Methods: Autopsy studies have revealed the characteristic misfolding of TDP-43 proteins in aged brains, illuminating the prevalence and distribution of TDP-43 in LATE. Additionally, recent research underscores the crucial role of impaired immune cells as key players in the neurodegeneration and the pathogenesis of TDP-43 proteinopathy. The systematic analysis of TDP-43 in LATE comprised 25 research findings with sample sizes ranging from 10 to 500 individuals.

Results: The objective of this review is to provide an extensive overview of the symptoms, neuropathological signs, proteinopathy, and approaches to diagnose LATE, with a focus on the way immune cell failure plays a role in its growth.

Discussion: This work aims to help comprehend LATE better by looking at how immune dysregulation and TDP-43 proteinopathy interact with each other. This will allow for new treatments that focus on immune pathways to help manage dementia.