Aβ peptide has dominated center stage in AD research, but the discovery last year of a tau mutation that causes a familial non-AD dementia has reawakened broader interest in tau. In Alzheimer’s disease, tau aggregates into pathological neurofibrillary tangles as a result of hyperphosphorylation. One theory attracting attention is the idea that tau becomes hyperphosphorylated due to a reactivation of cell cycle machinery in neurons.
Advocates of this view include Eva-Maria and Eckhard Mandelkow, who presented a cluster of papers further teasing apart the mechanisms that underlie tau phosphorylation (Abstracts 502.2-4). According to their data, MARK (microtubule affinity regulation kinase) phosphorylates tau at Ser262, which causes tau to detach from microtubules, thereby destabilizing them. The Mandelkows think that normally, destabilization allows neuronal processes to become dynamic and form new extensions. "Phosphorylation is a GOOD thing," is how Eva-Maria Mandelkow put it. They identified the KXGS repeat domain as the site which, if slightly phosphorylated, increases process outgrowth.
The Mandelkows went on to elucidate a phosphorylation pathway that gives rise to the Alzheimer's form of tau, as identified by the AT100 antibody. They reported that GSK3-β, acting on a PHF-like conformation of tau, followed by phosphorylation by PKA, is the only pathway that produces AD-type tau.
Finally, Eckhard Mandelkow described some preliminary findings indicating that tau may play a role in axonal transport. He sketched out a model in which tau, depending on its state of phosphorylation, may alter the equilibrium state of axonal transport. For example, he speculated, if the rate of retrograde transport were to outstrip that of anterograde transport, important molecules will not be able to reach the axon terminals.—June Kinoshita
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- De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, Schroeter EH, Schrijvers V, Wolfe MS, Ray WJ, Goate A, Kopan R. A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature. 1999 Apr 8;398(6727):518-22. PubMed.