12345678910111213141516171819202122Aβ级联效应假说（Theamyloidcascadehypothesis）242526人类tau蛋白基因位于17号染色体长臂上，长度在100kb以上，有16个外显子。Tau蛋白有6种变异体，分子量在48～67kD之间，它们是来源于同一单基因的不同mRNA剪辑产物，它们的区别在于C-末端有3或4个微管结合区以及N-末端有0、1或2个插入序列。已发现的21个异常过度磷酸化位点主要集中在N-末端(Ser-198～Thr-217)和C-末端(Ser-396～Ser-422)至微管结合重复区。有研究证实，完整的tau蛋白分子包括含有3～4个微管结合重复区的tau的6种变异体，它们的聚合作用可被外显子e2和e3所促进。A.Schematicrepresentationofthetauproteindomainsanditsphosphorylationsites,indicatingthehyperphosphorylatedsites(rectanglesinred)foundinpairedhelicalfilamentsinAD.Tauhyperphosphorylationsblockitscapacitytomodulatecytoskeletaldynamicsandpromotetauself-aggregationintoPHFsandtangles.ThemicrotubulebindingrepeatsaredenotedbyR1throughR4.B.Schematicrepresentationoftheamyloidprecursorproteinmajordomains,indicatingthesequenceofthe4-kDaAβpeptide(inorange)cleavedbysecretases.3031表2.PD研究的里程碑3334353637383940414243444546474849505152535455565758596061626364656667697071727374757677787980