Tauproteinsaremicrotubule-associatedprotein(MAPs)whichareabundantinneuronsofthecentralnervoussystem,butarealsoexpressedatverylowlevelsinCNSastrocytesandoligodendrocytesandelsewhere.Oneoftau"smainfunctionsistomodulatethestABIlityofaxonalmicrotubules.Tauisactiveprimarilyinthedistalportionsofaxonsprovidingmicrotubulestabilizationaswellasflexibility.PathologiesanddementiasofthenervoussystemsuchasAlzheimer"sdiseasefeaturetauproteinsthathavebecomedefectiveandnolongerstabilizemicrotubulesproperly.Asaresult,tauformsaggregateswithspecificstructuralpropertiesreferredtoasPairedHelicalFilaments(PHFs)thatareacharacteristicofmanydifferenttypesofdementias,knownastauopathies. Tauhastwoprimarywaysofcontrollingmicrotubulestability:isoformsandphosphorylation.Sixtauisoformsexistinhumanbraintissue,andtheyaredistinguishedbythenumberofbindingdomains.Threeisoformshavethreebindingdomainsandtheremainingthreehavefourbindingdomains.Thebindingdomainsarelocatedinthecarboxy-terminusoftheproteinandarepositively-charged(forbindingtothenegatively-chargedmicrotubule).Tauisoformswithfourbindingdomainsarebetteratstabilizingmicrotubulesthanthosewiththreebindingdomains. Thus,inthehumanbrain,thetauproteinsconstituteafamilyofsixisoformswiththerangefrom352-441aminoacids.Theyalsodifferineitherzero,oneortwoinsertsof29aminoacidsattheN-terminalpart(exon2and3),andthreeorfourrepeat-bindingregionsattheC-terminus.So,thelongestisoformintheCNShasfourrepeats(R1,R2,R3andR4)andtwoinserts(441aminoacidstotal),whiletheshortestisoformhasthreerepeats(R1,R3andR4)andnoinsert(352aminoacidstotal).Tauisalsoaphosphoproteinwith79potentialSerine(Ser)andThreonine(Thr)phosphorylationsitesonthelongesttauisoform.Phosphorylationhasbeenreportedonapproximately30ofthesesitesinnormaltauproteins.MechanismsthatdrivetaulesionformationinthehighlyprevalentsporADIcformofADarenotfullyunderstood,butappeartoinvolveabnormalpost-translationalmodifications(PTMs)thatinfluencetaufunction,stability,andaggregationpropensity.
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