Why do amyloid plaques cause Alzheimer’s disease? While it would seem to be self-evident that neurons would prefer not to be surrounded by tangled forest of malfolded, insoluble protein deposits, the mechanism by which these plaques cause neuronal death remains an active subject of inquiry.

Cell-autonomous mechanisms (i.e., those in which the plaques act directly on the neurons that will ultimately die, which are the same cells that produced the Aß and tau protein that make up the plaques) are likely to be most important, but some scholars have begun to consider the cell-non-autonomous possibilities. What if the primary action of amyloid plaques is on another type of cell entirely — such as the ubiquitous, essential, yet still poorly understood neuronal support cell, the microglia? Flanary et al. argue that the presence of amyloid plaques accelerates the process of microglial senescence:

Advanced age and presence of intracerebral amyloid deposits are known to be major risk factors for development of neurodegeneration in Alzheimer’s disease (AD), and both have been associated with microglial activation. However, the specific role of activated microglia in AD pathogenesis remains unresolved. Here we report that microglial cells exhibit significant telomere shortening and reduction of telomerase activity with normal aging in rats, and that in humans there is a tendency toward telomere shortening with presence of dementia. Human brains containing high amyloid loads demonstrate a significantly higher degree of microglial dystrophy than nondemented, amyloid-free control subjects. Collectively, these findings show that microglial cell senescence associated with telomere shortening and normal aging is exacerbated by the presence of amyloid. They suggest that degeneration of microglia is a factor in the pathogenesis of AD.

To summarize: Long-term activation of microglia exposed to amyloid results in telomere shortening (presumably the cells undergo more divisions than when they’re not activated), which ultimately leads to cellular senescence when telomeres become critically short. Consistent with this, senescent cells can be observed in amyloid brains, at higher levels than one would expect as a result of chronological age alone.

The authors do not demonstrate a direct connection to Alzheimer’s pathology, but it’s easy to build a model in which senescent microglia contribute to cell death. Evidence from our lab and others has shown that senescent cells, which accumulate throughout the body as a function of age and genotoxic damage, secrete high levels of dangerous signaling molecules, e.g., inflammatory cytokines, growth factors, and matrix metalloproteases. While the post-mitotic cells in the vicinity of senescent microglia are unlikely to respond to growth factors, the inflammatory factors and protease activity could easily conspire to make life quite unpleasant for the delicate neurons. This would be especially likely if the amyloid plaques are also causing direct damage to these cells.

Several labs are already considering ways to therapeutically eliminate senescent cells, either exploiting the body’s natural methods (immunologically) or using gene therapy. A firm connection between senescence and a scourge like Alzheimer’s (which, unlike aging as such, is already recognized by funding agencies as a pathology) could go a long way toward energizing such efforts.