Isoform-specific interactions of apolipoprotein E with microtubule-associated protein tau: Implications for Alzheimer disease

Warren J. Strittmatter, Ann M. Saunders, Michel Goedert, Karl H. Weisgraber, Li Ming Dong, Ross Jakes, David Y. Huang, Margaret Pericak-Vance, Donald Schmechel, Allen D. Roses

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436 Scopus citations

Abstract

The apolipoprotein E (apoE) type 4 allele (APOE4) is a susceptibility gene for late-onset familial and sporadic Alzheimer disease. ApoE is found in some neurofibrillary tangle-bearing neurons, one of the major pathologic hallmarks of the disease. Neurofibrillary tangles contain paired helical filaments formed from hyperphosphorylated microtubule-associated protein tau. In vitro, tau binds avidly to apoE3, but not to apoE4, forming a bimolecular complex. Tau phosphorylated with a brain extract does not bind either isoform. ApoE3 binds to the microtubule-binding repeat region of tau, which is also the region that is thought to cause self-assembly into the paired helical filament. Binding studies with fragments of ApoE demonstrate that the tau-binding region of apoE3 corresponds to its receptor-binding domain and is distinct from the region that binds lipoprotein particles or β/A4 peptide. Isoform-specific interactions of apoE with tau may regulate intraneuronal tau metabolism in Alzheimer disease and alter the rate of formation of paired helical filaments and neurofibrillary tangles.

Original languageEnglish (US)
Pages (from-to)11183-11186
Number of pages4
JournalProceedings of the National Academy of Sciences of the United States of America
Volume91
Issue number23
DOIs
StatePublished - Nov 8 1994
Externally publishedYes

ASJC Scopus subject areas

  • General

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