The tau hypothesis

The low-molecular-weight microtubule-associated protein, tau, has been implicated in the pathophysiology of AD and other CNS neurodegenerative diseases for which dementia and NFT formation is a common feature (e.g., FTDP linked to chromosome 17 (FTDP-17); Niemann-Pick disease type C).19 Tau plays an important role in axonal transport, stabilizing microtubules, a process regulated by phosphorylation at one or more of the 30 identified serine and threonine sites on the protein. Kinases known to phosphorylate tau include microtubule affinity-regulating kinase, cyclin-dependent kinase-5 (CDK-5), glycogen synthase kinase-3 (GSK-3), c-jun N-terminal kinase (JNK), protein kinase A, protein kinase C, and calcium/calmodulin-dependent protein kinase II. Dephosphorylation of tau occurs via protein phosphatase-1, -2A, and -2B activity as well as the prolyl isomerase, Pin 1. In pathological states, tau is hyperphosphorylated, which causes its dissociation from microtubules and aggregation into a fibrillar form, paired helical filaments, which further aggregate to constitute the NFT. In AD, dementia is more closely correlated with NFT formation than amyloid plaques; thus, mechanisms involved in NFT formation have been of interest for drug development, with selective kinase inhibitors and inhibitors of tau protein aggregation being potential targets.

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