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.
Department of Medicine (Neurology), Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Duke University Medical Center, Durham, NC 27710.
W J
WJ
Strittmatter
A M
AM
Saunders
M
M
Goedert
K H
KH
Weisgraber
L M
LM
Dong
R
R
Jakes
D Y
DY
Huang
M
M
Pericak-Vance
D
D
Schmechel
A D
AD
Roses
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