Aging slows breakdown of synaptic proteins, raising disease risk

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"In brief

• A new study reveals mechanisms linking synapse loss to cognitive decline and dementia in aging brains, highlighting critical changes during this process.
• Researchers found that aging slows the breakdown of synaptic proteins, leading to accumulation that may contribute to diseases like Alzheimer’s.
• Stanford’s innovative tagging method could enable tracking of neuronal proteins, facilitating the identification of new biomarkers for assessing brain health.

...

Now, researchers ... have discovered clues that may tie synapse loss to another hallmark of brain aging: the declining ability of brain cells to break down and recycle damaged proteins. ...

that synaptic proteins are particularly susceptible to this age-related garbage-disposal problem: In old age, synaptic proteins break down much more slowly, they become more likely to pile up into the tangled clumps of protein characteristic of neurodegenerative disease, and they are more likely to make their way into microglia, immune cells that prune away damaged synapses. ..."

From the abstract:

"Neurodegenerative diseases affect 1 in 12 people globally and remain incurable. Central to their pathogenesis is a loss of neuronal protein maintenance and the accumulation of protein aggregates with ageing.

Here we engineered bioorthogonal tools that enabled us to tag the nascent neuronal proteome and study its turnover with ageing, its propensity to aggregate and its interaction with microglia.

We show that neuronal protein half-life approximately doubles on average between 4-month-old and 24-month-old mice, with the stability of individual proteins differing among brain regions.

Furthermore, we describe the aged neuronal 'aggregome', which encompasses 1,726 proteins, nearly half of which show reduced degradation with age. The aggregome includes well-known proteins linked to diseases and numerous proteins previously not associated with neurodegeneration.

Notably, we demonstrate that neuronal proteins accumulate in aged microglia, with 54% also displaying reduced degradation and/or aggregation with age. Among these proteins, synaptic proteins are highly enriched, which suggests that there is a cascade of events that emerge from impaired synaptic protein turnover and aggregation to the disposal of these proteins, possibly through microglial engulfment of synapses. These findings reveal the substantial loss of neuronal proteome maintenance with ageing, which could be causal for age-related synapse loss and cognitive decline."

Aging slows breakdown of synaptic proteins, raising disease risk | Stanford Report "Recent research unveils new links between the brain’s waste management systems and neurodegeneration. The findings may provide insights for early disease identification."

Ageing promotes microglial accumulation of slow-degrading synaptic proteins (open access)

Images of mouse brain cells, with neurons in red and protein aggregates in green. Those protein aggregates are far more likely to form in older mice (right) compared with younger mice (left), which may contribute to slower breakdown of damaged proteins.