Deacidification of endolysosomes by neuronal aging drives synapse loss
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Deacidification of endolysosomes by neuronal aging drives synapse loss. / Burrinha, Tatiana; Cunha, César; Hall, Michael J.; Lopes-da-Silva, Mafalda; Seabra, Miguel C.; Guimas Almeida, Cláudia.
In: Traffic, Vol. 24, No. 8, 2023, p. 334-354.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Deacidification of endolysosomes by neuronal aging drives synapse loss
AU - Burrinha, Tatiana
AU - Cunha, César
AU - Hall, Michael J.
AU - Lopes-da-Silva, Mafalda
AU - Seabra, Miguel C.
AU - Guimas Almeida, Cláudia
N1 - Publisher Copyright: © 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
KW - aging
KW - endolysosomal system
KW - lysosome
KW - neuron
KW - synapses
U2 - 10.1111/tra.12889
DO - 10.1111/tra.12889
M3 - Journal article
C2 - 37218497
AN - SCOPUS:85159868625
VL - 24
SP - 334
EP - 354
JO - Traffic
JF - Traffic
SN - 1398-9219
IS - 8
ER -
ID: 348166192