Amyloid β Proteoforms Elucidated by Quantitative LC/MS in the 5xFAD Mouse Model of Alzheimer’s Disease

Soumya Kandi, Erika N. Cline, Brianna M. Rivera, Kirsten L. Viola, Jiuhe Zhu, Carlo Condello, Richard D. LeDuc, William L. Klein, Neil L. Kelleher*, Steven M. Patrie*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Numerous Aβ proteoforms, identified in the human brain, possess differential neurotoxic and aggregation propensities. These proteoforms contribute in unknown ways to the conformations and resultant pathogenicity of oligomers, protofibrils, and fibrils in Alzheimer’s disease (AD) manifestation owing to the lack of molecular-level specificity to the exact chemical composition of underlying protein products with widespread interrogating techniques, like immunoassays. We evaluated Aβ proteoform flux using quantitative top-down mass spectrometry (TDMS) in a well-studied 5xFAD mouse model of age-dependent Aβ-amyloidosis. Though the brain-derived Aβ proteoform landscape is largely occupied by Aβ1-42, 25 different forms of Aβ with differential solubility were identified. These proteoforms fall into three natural groups defined by hierarchical clustering of expression levels in the context of mouse age and proteoform solubility, with each group sharing physiochemical properties associated with either N/C-terminal truncations or both. Overall, the TDMS workflow outlined may hold tremendous potential for investigating proteoform-level relationships between insoluble fibrils and soluble Aβ, including low-molecular-weight oligomers hypothesized to serve as the key drivers of neurotoxicity. Similarly, the workflow may also help to validate the utility of AD-relevant animal models to recapitulate amyloidosis mechanisms or possibly explain disconnects observed in therapeutic efficacy in animal models vs humans.

Original languageEnglish (US)
Pages (from-to)3475-3488
Number of pages14
JournalJournal of Proteome Research
Issue number11
StatePublished - Nov 3 2023


  • 5xFAD
  • Alzheimer’s disease
  • amyloid β
  • top-down mass spectrometry
  • transgenic mouse model

ASJC Scopus subject areas

  • General Chemistry
  • Biochemistry


Dive into the research topics of 'Amyloid β Proteoforms Elucidated by Quantitative LC/MS in the 5xFAD Mouse Model of Alzheimer’s Disease'. Together they form a unique fingerprint.

Cite this