Aging slows the clearance of brain proteins and shifts synaptic debris toward microglia. This is what an experimental study published in Nature suggests, offering new insights to spark promising neuroscience research and a potential approach to age-related degenerative diseases.
The Study
Although the evidence is experimental, it warrants further investigation. Studies in mice appear to show that aging neurons struggle to clear synaptic proteins, shifting the burden onto microglia, which is thus exposed to a critical vulnerability in maintaining brain proteins.
Aging alters degradation, aggregation, and transfer of neuronal proteins to microglia. This is a process in which age is a dominant risk factor; aging makes neurons less capable of sustaining synthesis, folding, transport, and degradation of proteins, a collective process known as proteostasis.
Although several studies have analyzed protein turnover at the level of the whole brain, neurons are particularly sensitive since they must endure for a lifetime without dividing. To study the process, researchers used genetically modified mouse models in which selective labeling of newly synthesized neuronal proteins in living brains was achieved thanks to techniques such as BONCAT (Bioorthogonal Non-Canonical Amino Acid Tagging), which incorporates noncanonical amino acids into newly synthesized proteins via a tRNA synthetase.
Thus, young, middle-aged, and old mice were fed noncanonical, labeled amino acids using pulse-chase experiments to evaluate protein degradation over defined time intervals. In other experiments, the neuronal labeling mechanism was delivered using adeno-associated virus (AAV) vectors.
Diverse brain regions were dissected and analyzed, including cortex, hippocampus, striatum, and hypothalamus. The investigation also focused on how immune cells process neuronal proteins, using fluorescence-activated cell sorting (FACS) to isolate microglia and analyze neuron-derived proteins within these cells. It was thus possible to observe that neuronal protein degradation slows markedly with age across all examined brain regions.
On average, the protein half-life was nearly doubled between young and old mice, indicating a widespread age-related decline in protein turnover, particularly marked after middle age and depending on brain regions, most evident in the hippocampus and the sensory cortex. These changes were not explained by a reduced abundance of proteins, but by a general slowdown in the kinetics of neuronal protein degradation with aging.
Synaptic and Mitochondrial Proteins as Primary Targets
The proteins most affected by aging were found in greater amounts in synaptic structures, mitochondria, and cellular junctions—structures essential for neuronal communication and metabolic function. Many of these proteins were encoded by genes previously linked to neurodegenerative disorders and neurodevelopmental issues, suggesting a link between altered protein turnover and susceptibility to diseases.
Regional comparisons also showed that certain brain areas were more vulnerable to age-related proteostatic decline than others, mirroring irregular patterns of cognitive decline observed in humans. In addition to slowed degradation, aged neurons accumulated a large number of aggregated proteins.
A detailed analysis identified more than 1,700 neuronal proteins within insoluble aggregates in aged brains. Nearly half of these aggregated proteins also exhibited reduced degradation rates, indicating a close relationship between altered turnover and aggregation. Synaptic proteins were once again heavily overrepresented, reinforcing the idea that synapses are early and critical targets of age-related proteostatic failure.
Conversely and unexpectedly, microglia contained many proteins accumulated and slowly degraded that originated from neurons, with substantially higher levels in aged brains compared with young brains.
These proteins were enriched with synaptic markers and commonly localized within microglial lysosomes, indicating active uptake and processing. They represented both presynaptic and postsynaptic proteins, aligning with the microglial clearance of materials associated with synapses. More than 50% of neuronal proteins accumulated in aged microglia showed prior evidence of defective degradation or aggregation within neurons.
In conclusion, the experimental results suggest that microglia may act as a compensatory route for removing neuronal proteins when intrinsic neuronal degradation mechanisms are compromised.
However, because the burden of disposing neuronal proteins increases with age, this process could contribute to microglial stress and to greater age-related neuropathological vulnerability, with possible adverse consequences for brain health. While these results come from mouse models, they highlight neuronal proteostasis as a critical target for preserving brain function during aging.
Source
Guldner IH, Wagner VP, Moran-Losada P et al. Aging promotes microglial accumulation of slow-degrading synaptic proteins. Nature, 2026; 650, pages 930–941. DOI: 10.1038/s41586-025-09987-9
Abbonati a Karla Miller
