Site-specific dephosphorylation of tau of apolipoprotein E-deficient and control mice by M1 muscarinic agonist treatment

I. Genis, A. Fisher, D. M. Michaelson

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)206-213
Number of pages8
JournalJournal of Neurochemistry
Volume72
Issue number1
DOIs
StatePublished - 1999

Keywords

  • 1-Methylpiperidine-4-spiro-(2'-methylthiazoline)
  • AF150(S)
  • Apolipoprotein E
  • Dephosphorylation
  • M1 muscarinic agonist
  • Microtubule-associated protein
  • Tau

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