Examination of phosphorylated tau protein as a PHF-precursor at early stage Alzheimer's disease.

Hyperphosphorylated tau protein which can be isolated on the basis of insolubility in 1% sarkosyl (A68-tau fraction) is thought to represent a precursor pool for PHF assembly, associated histologically with neuritic pathology, which feeds into a more resistant tangle-associated PHF pool via cross-linking and proteolysis. We examined these predictions at the earliest detectable stages of neurofibrillary pathology. We report that there is no evidence that neuritic pathology represents an early pathologic stage, no evidence of an association between neuritic pathology and phosphorylated tau, no evidence of selective accumulation of phosphorylated tau at early stages of pathology, and no evidence for a precursor/product relationship between phosphorylated tau and PHFs during progression of pathology. We conclude that altered phosphorylation is a secondary process affecting 5% of PHFs and does not explain PHF assembly in Alzheimer's disease.

Short messages.

This paper has three purposes. The first one is to explain to a general audience what is involved in retrieving a web page or performing some other complex network transaction, and what can make it slow, and why the problem of slowness is likely to get worse as networked applications become more complex. The second is to describe, to those who program networked applications, certain facts that we have learnt from modelling communication networks, notably the fact of heavy-tailed distributions in traffic, which may allow more efficient applications to be written. The third is to describe to network modellers an interesting class of problems relating to algorithm design for communication networks.