A new study published in Traffic, by the Neuronal Trafficking in Aging group at NOVA Medical School, sheds light on some of the mechanisms involved in the loss of synapses in aging neurons.
In a recent research article published in the esteemed scientific journal Traffic, Cláudia Almeida’s group at NOVA Medical School, Neuronal Trafficking in Ageing Lab, has made a significant breakthrough in understanding the mechanisms behind synapse loss in aging neurons. Their findings uncover a previously unknown link between neuronal aging, endolysosome dysfunction, and the acidification of these cellular compartments, responsible for cell components “recycling”. The study's authors, including first author Tatiana Burrinha and also César Cunha, believe that these discoveries may pave the way for new therapeutic strategies to combat age-related neurodegenerative diseases such as Alzheimer's.
The research team focused their investigation on the endolysosomal system, which plays a critical role in waste management and recycling within cells. By analyzing aged neurons, the team observed that enlarged late-endocytic organelles, observed through the labelling of specific protein marker LAMP1+, accumulated near synapses in both aged neurons and the aged brain. This observation prompted further exploration into the functional changes occurring within these endolysosomes during neuronal aging.
"Our research delves into the effects of neuronal aging on endolysosomes, their ability to function optimally, and how it can impact synapses", explained Tatiana Burrinha. " Our findings reveal that as neurons age, the degradative abilities of endolysosomes decline due to lower acidification. Importantly, we discovered that aging lysosomes became more acidified and degradative by activating lysosomal calcium export, protecting synapses."
To further unravel the intricacies of this process, the researchers conducted experiments to manipulate the acidification levels of aged endolysosomes. Surprisingly, they found that increasing the acidification of these endolysosomes improved synapses, highlighting the direct correlation between endolysosome dysfunction and age-dependent synapse loss.
Principal Investigator Cláudia Almeida emphasized the significance of these findings: "As we age, our neurons lose their ability to function correctly, leading to the loss of synapses, making us more vulnerable to Alzheimer's disease. However, our research has discovered that therapeutically targeting endolysosome dysfunction can help delay or prevent the onset of neurodegenerative disorders like Alzheimer's."
When asked to provide an analogy to help explain their work, the scientists drew a parallel with waste management. “In our society, urban waste management, like cellular waste management of neurons, requires a highly complex system, including an efficient collection and effective sorting system to recycle as much as possible and optimize energy costs. However, waste management requires the active involvement of citizens that sort and recycle. The proper functioning of waste management improves public health, reducing the risk of soil and river contamination”, state the researchers, “despite the active involvement of lysosomes (citizens) in trying to manage waste, as citizens, endolysosomes age, accumulate damage, and become not fully functional, leading to the accumulation of "waste" and damaging neurons' health (synapse loss).”
The groundbreaking findings, of this study, in collaboration with Mafalda Silva from the Molecular Mechanisms of Disease lab and Michael Hall (iNOVA4Health) from NOVA Medical School, provide new insights into the intricate mechanisms underlying neuronal aging and synapse loss. By identifying the role of endolysosome dysfunction and acidification in this process, the researchers have opened up avenues for future therapeutic interventions targeting neurodegenerative diseases. As the understanding of the aging brain continues to expand, these findings offer hope for the development of innovative treatments to preserve cognitive function and improve the quality of life for aging populations.
Read the full article at the Traffic website:
Burrinha T, Cunha C, Hall MJ, Lopes-da-Silva M, Seabra MC, Guimas Almeida C. Deacidification of endolysosomes by neuronal aging drives synapse loss. Traffic. 2023 May 23. doi: 10.1111/tra.12889.
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