A previously unknown functional link between amyloid-β and (p-)tau, proteins that both play a major role in the development of Alzheimer's disease, has been demonstrated by a team led by Ising, Heneka et al (2019) in the scientific journal Nature.
In a healthy state, tau proteins are stabilizers for the skeleton of nerve cells. In the development of Alzheimer's disease, these proteins detach from the skeleton and clump together in the nerve cells, so that they can no longer fulfill their actual function of stabilization.
Ising et al (2019) report that they have discovered a “molecular switch” that provides more information about the point in time when the tau proteins begin to change (phosphorylate) and thus detach from the skeleton and clump together. This happens when the molecular switch (consisting of the protein complex NLRP3 inflammasome, which exists within immune cells of the brain) triggers the release of pro-inflammatory substances and causes hyperphosphorylation of tau proteins. The hyperphosphorylation then leads to the detachment of tau proteins from the nerve skeleton and to their aggregation (neurofibrillary tangles).
The study also showed that amyloid-β, which is deposited between nerve cells over years and long before a diagnosis of Alzheimer's disease, activates the molecular switch (NLRP3 inflammasome), which promotes further amyloid-β deposition and leads to the aggregation of Tau. This is new evidence for the currently most popular model “amyloid cascade hypothesis” for the development of Alzheimer's disease.
This publication is relevant to the IASON project as it provides information on the temporal development of Alzheimer's disease. The aim would therefore be to determine the “switching point” by early diagnosis via EEG in order to be able to intervene.
Update: Tau deposition even without previous amyloid-β
Kant & Ossenkoppele have shown that the development of manifest Alzheimer's dementia is not only caused by the deterministic sequence of amyloid-β accumulation with subsequent formation of p-tau, which is predominant in genetic disposition, but also by AD progression with p-tau accumulation independent of amyloid-β. Reference to the different paths of p-tau progression in AD, which Ossenkoppele writes about. The renowned researcher H. Braak has already established in 2011 that tau deposition can also occur in young people without prior amyloid-β agglomeration, see (Braak, 2011):
"In this sample under the age of 30, 41/42 cases did not have amyloid-b plaques or neuritic plaques (Table 1) The absence of amyloid-b deposition in these individuals is not compatible with the amyloid cascade hypothesis, which assumes that amyloid-b drives AD pathogenesis and secondarily induces intraneuronal tau changes “downstream”".
Here we would like to point out the update of the following point "The role of sleep & EEG", where it is shown that already one night of sleep deprivation at any age leads to an increase of the total tau level in the blood.
- Ising, C., Venegas, C., Zhang, S., Scheiblich, H., Schmidt, S. V., … & Heneka, M. T. (2019). NLRP3 inflammasome activation drives tau pathology. Nature 575, 669–673. https://doi.org/10.1038/s41586-019-1769-z
- Kant, R.v.d., Goldstein, R. S. B., Ossenkoppele, R. (2020). Amyloid-β-independent regulators of tau pathology in Alzheimer disease. Nature reviews, Neuroscience, Vol. 21. https://www.nature.com/articles/s41583-019-0240-3
- Braak, H., Tredici, K. d., (2011). The pathological process underlying Alzheimer’s disease in individuals under thirty. Acta Neuropathol (2011) 121:171–181. https://doi.org/10.1007/s00401-010-0789-4