Isoform-specific interactions of apolipoprotein E with microtubule-associated protein tau: implications for Alzheimer disease.
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 beta/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.
Strittmatter
W J
WJ
Department of Medicine (Neurology), Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Duke University Medical Center, Durham, NC 27710.
Saunders
A M
AM
Goedert
M
M
Weisgraber
K H
KH
Dong
L M
LM
Jakes
R
R
Huang
D Y
DY
Pericak-Vance
M
M
Schmechel
D
D
Roses
A D
AD
D000544:Alzheimer Disease / Q000503:physiopathology*; D001057:Apolipoproteins E / Q000737:chemistry*; D001665:Binding Sites; D006801:Humans; D066298:In Vitro Techniques; D010750:Phosphoproteins / Q000378:metabolism; D011485:Protein Binding; D011994:Recombinant Proteins; D016875:tau Proteins / Q000737:chemistry*
D001057:Apolipoproteins E; D010750:Phosphoproteins; D011994:Recombinant Proteins; D016875:tau Proteins