A decade before the distinguishing lesions of TDP-43 emerge, contributing to the neurodegenerative process and cognitive decline seen in LATE (Limbic-predominant Age-related TDP-43 Encephalopathy), molecular and cellular transformations are already underway. Research from the National Institute on Aging, presented in Acta Neuropathologica, indicates these early changes exert particular influence on the deterioration of memory and visual-spatial capabilities among the elderly.
LATE-NC is marked by harmful accumulations of the protein TDP-43, which manifest specific patterns within the brain, typically in individuals past their eightieth year. It is prevalent among those with advanced Alzheimer’s disease. In a state of health, TDP-43 resides within the cell’s nucleus—a membrane-bound structure safeguarding DNA—where it oversees genetic expression. However, in the case of LATE, TDP-43 abandons the nucleus, amassing instead within the cytoplasm. Earlier research connects the disruption of TDP-43’s role in gene splicing—a requisite process for the generation of protein variants—to the neuropathological changes characteristic of LATE-NC.
In a comprehensive investigation by the National Institute on Aging, Johns Hopkins University, and allied entities, scientists delved into the dynamic alterations of the TDP-43 protein within the senescent brain, its relation to LATE-NC, its ties with Alzheimer’s, and its overall impact on cognitive erosion. Parsing through the postmortem neural tissues gleaned from 309 individuals engaged in the Baltimore Longitudinal Study of Aging (BLSA)—whose ages spanned from 57 to 109 at their demise—the researchers identified the presence of LATE-NC in 38% of the cerebral specimens, noting a prevalence within brains heavily afflicted by Alzheimer’s. Yet, upon evaluating the BLSA’s cognitive data, it became apparent that the influence of LATE-NC on specific mnemonic and visual-spatial faculties operates distinctly from Alzheimer’s pathology.
The investigation then employed tailored antibodies to pinpoint TDP-43’s disposition within the autopsied cerebral matter. A striking discovery was that 14% of these brains exhibited a complete nuclear absence of TDP-43, yet no cytoplasmic agglomerations—this phenomenon presented exclusively in subjects in their fifties. This observation suggests a prelude to TDP-43 clustering by about a decade, a theory further affirmed upon scrutiny of an external demographic, ages 20 to 60, where no unusual TDP-43 activity arose in individuals below the fifty-year threshold.
Advancing their quest, the team probed the BLSA neural samples for certain RNA and protein derivatives that are the output of a gene under the governance of TDP-43. The inference was clear: brains with cytoplasmic TDP-43 manifested RNA and protein variants indicative of TDP-43 functionality loss. These same brains also exhibited markedly elevated tau tangle quantities—abnormalities closely interwoven with Alzheimer’s. It’s postulated by the researchers that the deterioration of TDP-43 activity within the nucleus may act as a fulcrum, exacerbating the accumulation of tau tangles and hastening neural decay. This collection of insights underpin the concept that TDP-43’s cytoplasmic relocalization and attendant functional impairment are indeed early events in the odyssey towards LATE-NC, occuring a substantial ten years prior to the emergence of detrimental TDP-43 clusters.