A number of lines of evidence implicate senescent microglia in the development of neurodegenerative conditions. Microglia are innate immune cells of the central nervous system, analogous to macrophages elsewhere in the body. Microglia appear to become more inflammatory with age, but this isn't just an amplification of inflammatory signaling that arises due to age-related dysfunctions such as mislocalization of mitochondrial DNA. Some microglia become senescent, and like other types of senescent cell, they energetically produce inflammatory signaling. Clearing such cells from the brain has produced benefits in animal models of neurodegeneration, but it remains to be seen as to whether that works well in humans.
The materials here summarize the work of researchers who suggest that failing autophagy is an important cause of microglial senescence in the aging brain. Autophagy is a collection of cell maintenance processes responsible for recycling damaged and worn proteins and cell components, sending them to a lysosome for disassembly by enzymes. It is well known that autophagy falters with advancing age, though a full accounting of why this is the case remains to be established. Inefficient autophagy leads to a greater burden of dysfunction in a cell, and, in principle, more cells tipped over the edge into a state of senescence.
The one caution here is that researchers essentially disabled autophagy rather than dialing it back to a lesser degree of efficiency. This produces a more obvious result, more easily measured, but the outright breakage of major mechanisms in a cell can lead to outcomes that are not reflective of what takes place inside the body as a result of a mere decline in efficiency. Still, one can look at this work in the context of other avenues of research that also implicate microglia and autophagy in the onset of neurodegeneration.
When deprived of their ability to dispose of detritus via autophagy, microglia become annoyed, transitioning into a senescent, dysfunctional state. That was the upshot of a recent study in which researchers used conditional knockout mice to disable the "self-eating" pathway in microglia. Some of the cells shut down their cell cycle and revved up secretion of cytokines - behavior typical of senescent cells. In amyloid-laden mice, these autophagy-deficient microglia refused to transition into a bona fide disease-associated microglia (DAM) state, failing to properly contain plaques or to protect nearby synapses from shriveling. The findings further raise the profile of microglial autophagy as an essential part of the brain's response to proteopathic insults.
Neurons suffer dramatic impairments in autophagy both in the Alzheimer's disease (AD) brain and in mouse models of amyloidosis. While neurons need autophagy to clean up their own waste, microglia need this pathway for an additional purpose, that is, to help them mop up protein aggregates and detritus spewed by sickly neurons. Recent studies have cast microglial autophagy - a bioenergetically demanding process - as quelling amyloid-β (Aβ) plaques, tau pathology, and neuroinflammation.
Researchers conditionally deleted, from wild-type mice, the Atg7 gene, which encodes a protein critical for autophagosome biogenesis, only from microglia. They knocked out Atg7 in 2-month-old mice, then examined their brains six months later. Using single-cell transcriptomics, the scientists detected eight gene-expression clusters of microglia in wild-type and Atg7-cKO mice. Zeroing in on one that was far more abundant in the conditional knockouts, they found a cadre of microglia that appeared to have transitioned into a senescent state.
In 5xFAD AD model mice given these conditional Atg7 knockouts, microglia also did not assume a DAM state, opting instead for a senescence-associated profile. "SAMs" expressing S100a4, a marker of this senescent profile, appeared disinterested in amyloid. As a result, Aβ sprawled into diffuse plaques, which were surrounded by hyperphosphorylated tau and dystrophic neurites. This suggests that, without autophagy available to them, microglia became recalcitrant and no longer contained Aβ plaque formation, allowing the aggregates to become more of a hazard to nearby neurons.
Finally, the researchers treated the double-transgenic mice with dasatinib and quercetin, a combination therapy with proposed senolytic effects. The treatment reduced the number of microglia that were clogged with a backlog of autophagy substrates and expressed senescence markers. The findings place autophagy upstream of the microglial transition to a beneficial, disease-associated state, the authors proposed. Considering reports that autophagy declines with age while senescent cells become more numerous, the authors blame this combination for the dearth of DAM-like cells detected in human AD brains.