Site-specific dephosphorylation of tau of apolipoprotein E-deficient and control mice by M1 muscarinic agonist treatment.
Apolipoprotein E (apoE)-deficient mice have memory deficits that are associated with synaptic loss of basal forebrain cholinergic projections and with hyperphosphorylation of distinct epitopes of the microtubule-associated protein tau. Furthermore, treatment of apoE-deficient mice with the M1 selective agonist 1-methylpiperidine-4-spiro-(2'-methylthiazoline) [AF150(S)] abolishes their memory deficits and results in recovery of their brain cholinergic markers. In the present study, we used a panel of anti-tau monoclonal antibodies to further map the tau epitopes that are hyperphosphorylated in apoE-deficient mice and examined the effects of prolonged treatment with AF150(S). This revealed that tau of apoE-deficient mice contains a distinct, hyperphosphorylated "hot spot" domain which is localized N-terminally to the microtubule binding domain of tau, and that AF150(S) has an epitope-specific tau dephosphorylating effect whose magnitude is affected by apoE deficiency. Accordingly, epitopes which reside in the hyperphosphorylated "hot spot" are dephosphorylated by AF150(S) in apoE-deficient mice but are almost unaffected in the controls, whereas epitopes which flank this tau domain are dephosphorylated by AF150(S) in both mice groups. In contrast, epitopes located at the N and C terminals of tau are unaffected by AF150(S) in both groups of mice. These findings suggest that apoE deficiency results in hyperphosphorylation of a distinct tau domain whose excess phosphorylation can be reduced by muscarinic treatment.
Genis
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Department of Neurobiochemistry, Tel Aviv University, Israel.
Fisher
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Michaelson
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DM
D000818:Animals; D000911:Antibodies, Monoclonal; D001057:Apolipoproteins E / Q000235:genetics*; D015153:Blotting, Western; D001923:Brain Chemistry / Q000235:genetics; D000939:Epitopes / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018721:Muscarinic Agonists / Q000494:pharmacology*; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology*; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic / Q000502:physiology*; D013844:Thiazoles / Q000494:pharmacology*; D016875:tau Proteins / Q000032:analysis / Q000276:immunology / Q000378:metabolism*
C111926:1-methylpiperidine-4-spiro-(2'-methylthiazoline); D000911:Antibodies, Monoclonal; D001057:Apolipoproteins E; D000939:Epitopes; D018721:Muscarinic Agonists; D010880:Piperidines; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic; D013844:Thiazoles; D016875:tau Proteins