Amyloid-β42 alters apolipoprotein E solubility in brains of mice with five familial AD mutations

Katherine Lynn Youmans, Steffi Leung, Juan Zhang, Erika Maus, Kathleen Baysac, Guojun Bu, Robert Vassar, Chunjiang Yu, Mary Jo LaDu

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Amyloid plaques composed of the 42 amino acid form of amyloid-β peptide (Aβ42) are a pathological hallmark of Alzheimer's disease (AD), but soluble and intraneuronal Aβ42 are the more proximal causes of synaptic dysfunction and neurotoxicity. Apolipoprotein E (apoE) modulates this disease process, as inheritance of the e{open}4 allele of the apoE gene is the primary genetic risk factor for AD. To address the solubility of Aβ42 and apoE, the 5xFAD-specific extraction profile for Aβ42 was optimized, a protein extraction protocol was optimized in the presence of minimal to extensive Aβ42 pathology. Sequential extractions with TBS, TBS. +. Triton X-100 (TBSX), and guanidine-HCl (GuHCl) or formic acid (FA) were used with tissue from young and old wild type or mice expressing 5 familial AD mutations (5xFAD), in disease-susceptible or -resistant brain regions. In older 5xFAD mice, the extraction of insoluble Aβ42 and m-apoE protein was increased with FA compared to GuHCl. The 5 FAD mutations significantly increase production of Aβ42, recapitulating AD-like pathology at a greatly accelerated rate. Consistent protein extraction and the specificity of extractions for soluble or membrane-associated proteins were demonstrated. Age-dependent increases in Aβ42 were observed in all extraction fractions, particularly in the cortex and hippocampus. In both young and old 5xFAD mice, Aβ42 is TBS- or GuHCl-soluble. While in WT mice m-apoE is TBSX-soluble, in 5xFAD mice m-apoE is TBS- or GuHCl-soluble. Thus, the 5xFAD-specific extraction profile of Aβ42 paralleled that of m-apoE. As now characterized, this method identifies the extraction profile for disease relevant apoE and Aβ in the brain, both normal or modified due to neuropathological processes.

Original languageEnglish (US)
Pages (from-to)51-59
Number of pages9
JournalJournal of Neuroscience Methods
Volume196
Issue number1
DOIs
StatePublished - Mar 15 2011

Keywords

  • 5xFAD
  • Alzheimer's disease
  • ApoE
  • Detergent
  • Solubility

ASJC Scopus subject areas

  • Neuroscience(all)

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