Spliceosome protein alterations differentiate hubs of the default mode connectome during the progression of Alzheimer's disease

Document Type

Article

Abstract

Default mode network (DMN) is comprised in part of the frontal (FC), precuneus (PreC), and posterior cingulate (PCC) cortex and displays amyloid and tau pathology in Alzheimer's disease (AD). The PreC hub appears the most resilient to AD pathology, suggesting differential vulnerability within the DMN. However, the mechanisms that underlie this differential pathobiology remain obscure. Here, we investigated changes in RNA polymerase II (RNA pol II) and splicing proteins U1-70K, U1A, SRSF2, and hnRNPA2B1, phosphorylated AT8 tau, 3R and 4Rtau isoforms containing neurons and amyloid plaques in layers III and V-VI in FC, PreC, and PCC obtained from individuals with a preclinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), and mild/moderate mAD. We found a significant increase in pS5-RNA pol II levels in FC NCI, U1-70K in PreC MCI and mAD, and hnRNPA2B1 and SRSF2 levels in PCC mAD. 1N3Rtau levels were significantly increased in FC, decreased in PreC in mAD, and unchanged in PCC, whereas 1N4Rtau increased in mAD across the hubs. SRSF2, U1-70K, U1A, and hnRNPA2B1 nuclear optical density (OD), size, and number were unchanged across groups in FC and PCC, while PreC OD hnRNPA2B1 was significantly greater in mAD. Mislocalized U1A and U1-70K tangle-like structures were found in a few PCC cases and colocalized with AT8-bearing neurofibrillary tangles (NFTs). FC pS5-RNA pol II, PreC U1-70K, Pre pS5,2-RNA pol II, and PCC hnRNPA2B1 and SRSF2 protein levels were associated with cognitive decline but not neuropathology across clinical groups. By contrast, splicing protein nuclear OD measures, size, counts, and mislocalized U1-70K and U1A NFT-like structures were not correlated with NFT or plaque density, cognitive domains, and neuropathological criteria in DMN hubs. Findings suggest that RNA splicing protein alterations and U1 mislocalization contribute differentially to DMN pathogenesis and cognitive deterioration in AD.

Keywords

RNA polymerase, cognitive decline, mild cognitive impairment, neurofibrillary tangles, plaque pathology, splicing proteins

Medical Subject Headings

Humans; Alzheimer Disease (pathology, metabolism); Aged; Male; Female; Disease Progression; Cognitive Dysfunction (pathology, metabolism); Spliceosomes (metabolism, pathology); Connectome; Aged, 80 and over; tau Proteins (metabolism); Default Mode Network (pathology, metabolism); Serine-Arginine Splicing Factors (metabolism); RNA Polymerase II (metabolism); Brain (pathology, metabolism)

Publication Date

9-1-2025

Publication Title

Brain pathology (Zurich, Switzerland)

E-ISSN

1750-3639

Volume

35

Issue

5

First Page

e70004

PubMed ID

40122679

Digital Object Identifier (DOI)

10.1111/bpa.70004

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