Brain region- and solubility-dependent proteomic signatures of neurofibrillary tangle pathology in Alzheimer's disease
- 1University of Pittsburgh
Abstract
Neurofibrillary tangles (NFTs) containing hyperphosphorylated tau proteins are a hallmark neuropathology of Alzheimers disease. However, the molecular basis underlying their spatial heterogeneity and biochemical complexity remain unclear. To address this, we performed mass spectrometry-based proteomic profiling of two neocortical regions with different susceptibilities to NFT pathology--the inferior temporal (IT) and middle frontal (MF) cortices--from 27 autopsy cases stratified by Braak NFT stage (Low 0-II, n=8; Mid III-IV, n=11; High V-VI, n=8). Brain homogenates were sequentially fractionated using buffers of increasing solubility (TBS, Na2CO, and Urea), followed by trypsin digestion and analysis by nanoLC-MS/MS with data-independent acquisition. Proteins were identified using PEAKS Studio 12 and linear mixed-effects models were applied to assess Braak stage-associated and region-specific changes in protein abundance and solubility. A total of 5,573 protein groups were identified, including 452 differentially expressed proteins (DEPs), 183 bidirectional expression proteins (BEPs), and 693 differentially soluble proteins (DSPs) associated with NFT pathology. These proteins were enriched in pathways related to cytoskeletal organization, synaptic transmission, metabolism, vesicular trafficking, and proteostasis. Marked regional differences were observed, with limited overlap between IT and MF across DEPs, BEPs, and DSPs. Protein change in MF was dynamic with a higher number of BEPs and suggested active cytoskeletal remodeling, whereas IT showed fewer BEPs and evidence of structural disruption, including alterations in intermediate filament components, consistent with vulnerability of IT and possible compensatory/plasticity changes in MF cortex. MF cortex had the greatest downregulation of DEPs between Low and Mid Braak stages, while the transition from Mid to High Braak stage showed upregulation of most of DEPs in both regions. In addition, widespread changes in protein solubility were observed, particularly decreased solubility at later Braak stages, implicating disruption of proteostasis. Together, these findings highlight region- and stage-dependent proteomic alterations associated with tau pathology and underscore their relevance for understanding disease mechanisms and informing biomarker development.
Related
- Associations between neuropsychiatric symptoms and cerebrospinal fluid amyloid pathology, and convergent proteomic signatures in Alzheimer’s disease
- Comprehensive Molecular Profiling for Precision Diagnostics: Integrating Genomic, Proteomic, and Epigenetic Landscapes in Human Pathology
- Megakaryocytic proteomic signatures define myeloproliferative neoplasms
- Neuropsychiatric symptom clusters and plasma proteomic signatures across cognitive ageing and dementia in Kinshasa, Democratic Republic of the Congo: a cross-sectional analysis of the EVCD-RDC cohort
- Proteomic machine-learning signatures associated with carotid plaque: A population-based hypothesis-generating study
BibTeX
@misc{zeng2026brain,
title = {{Brain region- and solubility-dependent proteomic signatures of neurofibrillary tangle pathology in Alzheimer's disease}},
author = {X. Zeng and E. Abrahamson and W. G. Balogun and J. K. Kofler and W. Paljug and V. N. Pivtoraiko and M. D. Ikonomovic and T. K. Karikari},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.04.26361149},
url = {https://www.medrxiv.org/content/10.64898/2026.10.04.26361149v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Brain region- and solubility-dependent proteomic signatures of neurofibrillary tangle pathology in Alzheimer's disease
AU - X. Zeng
AU - E. Abrahamson
AU - W. G. Balogun
AU - J. K. Kofler
AU - W. Paljug
AU - V. N. Pivtoraiko
AU - M. D. Ikonomovic
AU - T. K. Karikari
PY - 2026
DA - 2026/10/04
PB - medRxiv
DO - 10.64898/2026.10.04.26361149
UR - https://www.medrxiv.org/content/10.64898/2026.10.04.26361149v1
AB - Neurofibrillary tangles (NFTs) containing hyperphosphorylated tau proteins are a hallmark neuropathology of Alzheimers disease. However, the molecular basis underlying their spatial heterogeneity and biochemical complexity remain unclear. To address this, we performed mass spectrometry-based proteomic profiling of two neocortical regions with different susceptibilities to NFT pathology--the inferior temporal (IT) and middle frontal (MF) cortices--from 27 autopsy cases stratified by Braak NFT stage (Low 0-II, n=8; Mid III-IV, n=11; High V-VI, n=8). Brain homogenates were sequentially fractionated using buffers of increasing solubility (TBS, Na2CO, and Urea), followed by trypsin digestion and analysis by nanoLC-MS/MS with data-independent acquisition. Proteins were identified using PEAKS Studio 12 and linear mixed-effects models were applied to assess Braak stage-associated and region-specific changes in protein abundance and solubility. A total of 5,573 protein groups were identified, including 452 differentially expressed proteins (DEPs), 183 bidirectional expression proteins (BEPs), and 693 differentially soluble proteins (DSPs) associated with NFT pathology. These proteins were enriched in pathways related to cytoskeletal organization, synaptic transmission, metabolism, vesicular trafficking, and proteostasis. Marked regional differences were observed, with limited overlap between IT and MF across DEPs, BEPs, and DSPs. Protein change in MF was dynamic with a higher number of BEPs and suggested active cytoskeletal remodeling, whereas IT showed fewer BEPs and evidence of structural disruption, including alterations in intermediate filament components, consistent with vulnerability of IT and possible compensatory/plasticity changes in MF cortex. MF cortex had the greatest downregulation of DEPs between Low and Mid Braak stages, while the transition from Mid to High Braak stage showed upregulation of most of DEPs in both regions. In addition, widespread changes in protein solubility were observed, particularly decreased solubility at later Braak stages, implicating disruption of proteostasis. Together, these findings highlight region- and stage-dependent proteomic alterations associated with tau pathology and underscore their relevance for understanding disease mechanisms and informing biomarker development.
ER -