Background: Neurofibrillary tangles (NFT), consisting of hyperphosphorylated tau aggregates, are one of the major pathological hallmarks of Alzheimer's disease (AD). The burden of NFTs correlates with cognitive decline, and in vivo detection of NFT may help predict the clinical progression of AD. Mass spectrometry-based proteomic analysis of brain regions affected by NFTs holds the potential to unveil the molecular mechanisms underlying tau pathogenesis and uncover novel diagnostic/prognostic biomarkers and therapeutic targets.
Method: Post-mortem frozen samples of inferior temporal and middle frontal cortex were collected from 9 cases with different severity of tau pathology assessed by Braak NFT stage. Proteins were fractionated into three fractions using sequential extraction with lysis buffers with different solubility strengths (TBS, Na2CO3, and Urea), trypsin-digested, and analyzed using label-free nano-flow liquid chromatography-tandem mass spectrometry (nano LC-MS/MS). Linear mixed models were employed to assess the significance of proteins showing a differential abundance in tissues with Braak NFT stages 0-III and IV-VI or displaying Braak stage-dependent solubility changes.
Result: A total of 64908 peptides originating from 5475 protein groups were identified through the analysis of 18 brain tissue samples. Differential proteomic analysis revealed several proteins with significantly varied abundance in tissues with different severity of tau pathology. The most significant proteins among these include COL25A1, SNRNP70, MDK, ASPRV1, CLMN, DOCK5, HTRA1, LNPEP, SQSTM1 and Aβ peptides. Additionally, a number of proteins exhibited Braak-stage dependent solubility change; a significant subset of these proteins, including SNRNP70, SNRPGP15, PRPF6, SNRPE, SNRPD1, SNRPB, and SNRPD3, is involved in the spliceosome-mediated mRNA splicing.
Conclusion: Our study reveals numerous proteins exhibiting a significant association with tau pathology. These results align well with published findings that suggest the involvement of alternative splicing in reprogramming gene expression in the pathogenesis of AD. Further validation will be needed to assess their potential as therapeutic targets and/or diagnostic/prognostic biomarkers for AD pathologies.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1002/alz.092740 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Reversal of neuronal tau pathology via adiponectin receptor activation.
Commun Biol
January 2025
Division of Geriatrics, Department of Medicine, SMPH, University of Wisconsin-Madison, Madison, WI, USA.
Changes in brain mitochondrial metabolism are coincident with functional decline; however, direct links between the two have not been established. Here, we show that mitochondrial targeting via the adiponectin receptor activator AdipoRon (AR) clears neurofibrillary tangles (NFTs) and rescues neuronal tauopathy-associated defects. AR reduced levels of phospho-tau and lowered NFT burden by a mechanism involving the energy-sensing kinase AMPK and the growth-sensing kinase GSK3b.
View Article and Find Full Text PDFAnti-herpetic tau preserves neurons via the cGAS-STING-TBK1 pathway in Alzheimer's disease.
Cell Rep
December 2024
School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 9112102, Israel; Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA. Electronic address:
Alzheimer's disease (AD) diagnosis relies on the presence of extracellular β-amyloid (Aβ) and intracellular hyperphosphorylated tau (p-tau). Emerging evidence suggests a potential link between AD pathologies and infectious agents, with herpes simplex virus 1 (HSV-1) being a leading candidate. Our investigation, using metagenomics, mass spectrometry, western blotting, and decrowding expansion pathology, detects HSV-1-associated proteins in human brain samples.
View Article and Find Full Text PDFVascular endothelial growth factor receptor-1 (FLT1) interactions with amyloid-beta in Alzheimer's disease: A putative biomarker of amyloid-induced vascular damage.
Neurobiol Aging
December 2024
Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA; Pharmacology Department, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA; Epidemiology Doctoral Program, School of Medicine, Vanderbilt University, Nashville, TN, USA; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address:
We have identified FLT1 as a protein that changes during Alzheimer's disease (AD) whereby higher brain protein levels are associated with more amyloid, more tau, and faster longitudinal cognitive decline. Given FLT1's role in angiogenesis and immune activation, we hypothesized that FLT1 is upregulated in response to amyloid pathology, driving a vascular-immune cascade resulting in neurodegeneration and cognitive decline. We sought to determine (1) if in vivo FLT1 levels (CSF and plasma) associate with biomarkers of AD neuropathology or differ between diagnostic staging in an aged cohort enriched for early disease, and (2) whether FLT1 expression interacts with amyloid on downstream outcomes, such as phosphorylated tau levels and cognitive performance.
View Article and Find Full Text PDFTau phosphorylation suppresses oxidative stress-induced mitophagy via FKBP8 receptor modulation.
PLoS One
January 2025
Department of Anesthesiology & Perioperative Medicine, University of Rochester, Rochester, New York, United States of America.
Neurodegenerative diseases are often characterized by mitochondrial dysfunction. In Alzheimer's disease, abnormal tau phosphorylation disrupts mitophagy, a quality control process through which damaged organelles are selectively removed from the mitochondrial network. The precise mechanism through which this occurs remains unclear.
View Article and Find Full Text PDFDrugs repurposing in the experimental models of Alzheimer's disease.
Inflammopharmacology
January 2025
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, ElKasr Elaini Street, Cairo, 11562, Egypt.
The currently approved drugs for Alzheimer's disease (AD) are only for symptomatic treatment in the early stages of the disease but they could not halt the neurodegeneration, additionally, the safety profile of the recently developed immunotherapy is a big issue. This review aims to explain the importance of the drugs repurposing technique and strategy to develop therapy for AD. We illustrated the biological alterations in the pathophysiology of AD including the amyloid pathology, the Tau pathology, oxidative stress, mitochondrial dysfunction, neuroinflammation, glutamate-mediated excitotoxicity, insulin signaling impairment, wingless-related integration site/β-catenin signaling, and autophagy.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!