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Deacidification of endolysosomes by neuronal aging drives synapse loss

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Burrinha, Tatiana, Cunha, César, Hall, Michael J., Lopes‐da‐Silva, Mafalda, Seabra, Miguel C., Guimas Almeida, Cláudia·2023·Traffic
DOI 10.1111/tra.12889

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Abstract

Previously, we found that age‐dependent accumulation of beta‐amyloid is not sufficient to cause synaptic decline. Late‐endocytic organelles (LEOs) may be driving synaptic decline as lysosomes (Lys) are a target of cellular aging and relevant for synapses. We found that LAMP1‐positive LEOs increased in size and number and accumulated near synapses in aged neurons and brains. LEOs' distal accumulation might relate to the increased anterograde movement in aged neurons. Dissecting the LEOs, we found that late‐endosomes accumulated while there are fewer terminal Lys in aged neurites, but not in the cell body. The most abundant LEOs were degradative Lys or endolysosomes (ELys), especially in neurites. ELys activity was reduced because of acidification defects, supported by the reduction in v‐ATPase subunit V0a1 with aging. Increasing the acidification of aged ELys recovered degradation and reverted synaptic decline, while alkalinization or v‐ATPase inhibition, mimicked age‐dependent Lys and synapse dysfunction. We identify ELys deacidification as a neuronal mechanism of age‐dependent synapse loss. Our findings suggest that future therapeutic strategies to address endolysosomal defects might be able to delay age‐related synaptic decline.

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  • Lysosomes are critical for apoptosis in two ways: lysosomal membrane permeabilization releases hydrolases into cytosol; dying cell must be engulfed by neighboring astrocytes and microglia into phagosomes, fuse with lysosomes, and be digested by lysosomal enzymes.

    “Lysosomes are critical for apoptosis in two ways. In the cell undergoing apoptosis, the lysosomal membrane is permeabilized in a controlled fashion, allowing the release of lysosomal hydrolases into the cytosol.23 To complete the process, the dying cell must be engulfed by neighboring astrocytes and microglia into phagosomes, fuse24,25with their lysosomes, and then be digested and cleared by lysos”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [24]

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Authors
Burrinha, T., Cunha, C., Hall, M. J., Lopes‐da‐Silva, M., Seabra, M. C., & Guimas Almeida, C.
Affiliations
  • Universidade Nova de Lisboa (PT)
  • University of Copenhagen (DK)
  • iNOVA4Health, NOVA Medical School Faculdade de Ciências Médicas Universidade Nova de Lisboa Lisboa Portugal
ORCID
Venue
Traffic
Publisher
Wiley
Published
2023-05-23
Volume
24
Issue
8
Pages
334-354
ISSN
  • 1398-9219 (ISSN-L)
  • 1600-0854
DOI
10.1111/tra.12889
OpenAlex
W4377565028
Cited by
35
References
11
Citations by year
2026: 11 · 2025: 12 · 2024: 9 · 2023: 3
FWCI
5.06
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Traffic (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
  • Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, other-oa)
Funders
  • Alzheimer's Association (ALZ AARG‐19‐618007)
  • Fundação para a Ciência e a Tecnologia (iNOVA4Health‐UID/Multi/04462/2019, CEECIND/01536/2018, SFRH/BD/131513/2017, CEECIND/00410/2017, InvestigatorFCT‐IF/00998/2012)
  • European Regional Development Fund (PPBI‐POCI‐01‐0145‐FEDER‐022122)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
Keywords
neuronal aging, endolysosomes, lysosomal acidification, synaptic loss, V-ATPase, LAMP1, lysosomal degradation, neurites
MeSH terms
Adenosine Triphosphatases, Lysosomes, Neurons, Endosomes, Synapses

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