Is necroptosis a key mechanism of cell death in Alzheimer’s?

Cells can die for a variety of reasons. Some of them are intentional (“programmed”) in response to exposure to external stressors (like viral or toxic molecules) or internal problems (like DNA damage). And some of them are unintentional (“non-programmed”), which often involves the premature breakdown of cell membranes and loss of cell contents.

The totally simple necroptosis cell death pathway, from the NIH via Wikipedia

Caccamo et al recently published a paper suggesting that one specific type of programmed cell death, necroptosis, might be a key part of what mediates neuron death in Alzheimer’s disease (AD).

Their evidence spanned multiple human data sets of postmortem AD brains and mouse models (5XFAD), and showed that markers for necroptosis (MLKL, RIP1, RIP3) were often significantly correlated with the degree of AD neuropathology seen in those brains.

Notably, their data didn’t provide strong evidence to exclude apoptosis and non-necroptosis necrotic cell death pathways as also contributory to cell death in AD.

So, another study that would also be interesting would be to see a more global comparison of all different types of cell death, to see which markers correlate the strongest with AD neuropathologic changes.

On the other hand, the authors note in their discussion that there is a lot of cross-talk between necrosis and apoptosis, which means that it may be difficult or not make sense to distinguish between them in this way.

Even if necroptosis is the mechanism of cell death in AD, that doesn’t mean that we can just turn off this cell death pathway and rescue neurons and memory. If anything, it suggests that the neurodegeneration itself is intentional, likely helpful to mitigate even more damage, and that changes to stop AD will have to occur much farther up to pathogenic cascade.

Still, it’s critical to understand exactly what is the pathway of degeneration in AD so that we can figure out what to target, and this study might be an important part of that.