Subtyping based on hippocampal cryptic exon burden reveals proteome-wide changes associated with TDP-43 and Alzheimer's disease pathology - PubMed
4 hours ago
- #Alzheimer's disease
- #TDP-43
- #proteomics
- Subtyping based on hippocampal cryptic exon (CE) burden reveals proteome-wide changes linked to TDP-43 and Alzheimer's disease (AD) pathology.
- Study analyzed postmortem hippocampal tissue from 90 individuals, including controls and cases with LATE-NC, ADNC, and ADNC+LATE-NC.
- ADNC+LATE-NC cases exhibited the highest levels of cryptic exon inclusion, which correlated with phosphorylated TDP-43 (pTDP-43) but was more strongly intercorrelated among CE measures.
- CE burden defined low, intermediate, and high subtypes, largely independent of amyloid and tau pathology.
- Proteomic analyses showed reduced abundance of CE-target proteins and disruption of synaptic, endosomal, and RNA-binding pathways in high CE cases.
- Findings were supported by changes observed in TDP-43-depleted human i3Neurons, indicating biological relevance.
- CE burden serves as a robust molecular classifier for TDP-43 dysfunction in both LATE-NC and ADNC.