Senescence as an Amyloid Cascade: The Amyloid Senescence Hypothesis
Aβ Hypothesis
Aβ oligomers are thought to be the major driver of AD. However, the fact that their removal by antibodies does not affect disease progression can be used as an argument against this hypothesis. Senolytics were then proposed as an alternative treatment strategy that worked because it did not use the Aβ pathway, but it has been shown to work in both the tau and Aβ pathways. It could be that Aβ triggers a cascade that is then unaffected by the removal of AβO because they appear up to 25 years before the symptoms of AD. This cascade may be senescence itself.
They argue that AβO is a Stress induced premature senescence inducer. It could mediate cell-cycle reentry in neurons resulting in senescence.
Ways to induce senescence:
- Induce neurons to reenter the cell cycle which then leads to neuronal senescence.
- Induce the production of ROS that leads to senescence. This can be using aberrant activation of post-synaptic receptors or independent of receptor activation.
After the induction of senescence, neurons develop SASP which then leads to inflammation, tau pathology and secondary senescence and disease spread.
Final proposed model including immune response to senescence:
- AβO appears 15 to 25 years before the clinical onset of AD AβO induces
- senescence in neurons, but natural killer cells cannot enter the longer works since the senescence is irreversible
- with age related loss of the blood brain barrier functionality, NK cells enter the brain parenchyma and clear the many senescent cells leading to the onset of clinical AD. The potential for AβO to induce senescence must not be discounted.
tags: Aβ hypothesis, senolytics, senescence, amyloid cascade, alzheimer’s, immume response