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 microtubuleassociated protein tau. Furthermore, treatment of apoEdeficient mice with the M1 selective agonist 1-methylpiperidine-4-spiro-(2Ј-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. Key Words: Tau-Microtubule-associated protein-Dephosphorylation-Apolipoprotein E-M1 muscarinic agonist-1-Methylpiperidine-4-spiro-(2Ј-methylthiazoline)-AF150(S).
Apolipoprotein-E-deficient mice provide a useful model system for studying the role of apolipoprotein E (apoE) in brain function. In the present study, we characterized the cholinergic function of these mice and the extent of phosphorylation of their cytoskeletal protein tau. Morris water maze tasks revealed deficits in working memory that were accompanied by a specific decrease in hippocampal and cortical choline acetyltransferase activities. Immunoblot experiments utilizing native and dephosphorylated tau and antibodies directed against specific phosphorylated and unphosphorylated tau epitopes revealed that tau of the apoE-deficient mice is hyperphosphorylated. These results show that apoE-deficient mice have cognitive cholinergic and cytoskeletal derangements and point out the importance of this model for studying the role of apoE in neuronal function.
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