Trends in Neurosciences
Volume 25, Issue 1, 1 January 2002, Pages 22-26
Journal home page for Trends in Neurosciences

Opinion
Alzheimer's disease – do tauists and baptists finally shake hands?

https://doi.org/10.1016/S0166-2236(00)02031-2Get rights and content

Abstract

The amyloid cascade hypothesis has been the predominant model of molecular pathogenesis in Alzheimer's disease. The finding of tau mutations in other dementias has added weight to the hypothesis as it suggests that tau-pathology is a downstream but essential part of the dementing process. However, some observations remain difficult to reconcile with the hypothesis. In transgenic mice, for example, amyloid generation does not induce the predicted cascade and in man, plaques and tangles are separated temporally and spatially. One alternative possibility is that some common factor, loss of wnt signalling for example, might induce both plaques and tangles.

Section snippets

The ‘amyloid cascade hypothesis’

This was first formulated over a decade ago and centres around the Aβ peptide that is the main component of plaques. This peptide is derived from the membrane bound amyloid precursor protein (APP) which can be processed via two distinct processing pathways: the amyloidogenic pathway that liberates the Aβ peptide and the non-amyloidogenic pathway which precludes the formation of Aβ and instead generates a secreted form of APP, sAPPα [2]. The proponents of the amyloid cascade hypothesis (Fig. 1)

The tau and tangle hypothesis

The persuasiveness of the amyloid cascade hypothesis was so great that it led some to question whether the other main neuropathological lesion, neurofibrillary tangles, was perhaps an epiphenomenon. However, there was a small, but persistent, group that argued that tangles were in fact central to AD. Tangles are comprised of the microtubule associated protein tau, normally expressed in axons but which in AD becomes highly phosphorylated and aggregated into abnormal filaments in the cell body

An abnormality in the wnt signalling pathway might give rise to both pathologies

At this point the baptists and the tauists do indeed shake hands and yet there remains something lacking from the ‘amyloid cascade to tau hypothesis’. One plausible missing factor is vascular disease that, for example, augments tau phosphorylation in some regions early in the disease process (albeit reducing PHF formation in other regions in more severe disease) [46]. Some have proposed that it is the combination of vascular and Alzheimer's disease that is causal in dementia 47, 48. An

Conclusions

Neither the additional factor hypotheses, such as hypoxia, nor the common signalling pathway hypotheses, such as we suggest with wnt, fully resolve the anomaly in the ‘amyloid cascade to tau hypothesis’, namely that mutations in APP give rise to plaques and tangles in man but only plaques in mice. Resolving this anomaly is, however, of considerable importance if therapies are to be developed that are equally efficacious for patients who fit the ‘amyloid cascade to tau hypothesis’ and those who

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