Biology subjects

Burrinha, T.

Publications and source records attributed to Burrinha, T..

3 recordsLinked to original sources

bioRxiv2022

Deacidification of distal lysosomes by neuronal aging drives synapse loss

Previously, we found that age-dependent beta-amyloid accumulation is not enough to cause synaptic decline. Here, we characterized endolysosomes (late-endosomes and lysosomes) in aged neurons and the aged brain, which might drive synaptic decline since lysosomes are a cellular aging target and relevant for synapses. Neuronal aging induces enlarged endolysosome accumulation in the aged neurons and brain, especially distally, related to the increased anterograde movement. Aged lysosomes abound in neurites but are less degradative due to deacidification despite cathepsin D buildup, leading to late-endosome accumulation. Increasing the acidification of aged lysosomes by ML-SA1 treatment increased degradation and reverted synaptic decline, while lysosome alkalinization by chloroquine treatment mimicked age-dependent lysosome dysfunction and synaptic decline. We identify the deacidification of distal lysosomes as a neuronal mechanism of age-dependent synapse loss. Our findings suggest that future therapeutic strategies to address lysosomal defects might be able to delay age-related synaptic decline. HighlightsO_LIEnlarged endolysosomes accumulate close to synapses in aged neurons and aged brain C_LIO_LILate-endosomes accumulate with neuronal aging C_LIO_LIAged lysosomes are less acidic and degradative despite accumulating Cathepsin D C_LIO_LIIncreasing acidification of aged lysosomes improves synapses, while deacidification recapitulates age-dependent synapse loss C_LI SummaryWe identify the downregulation of the lysosome degradative activity via deacidification as a neuronal aging mechanism contributing to aging-dependent synapse loss. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=130 SRC="FIGDIR/small/511921v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@808d15org.highwire.dtl.DTLVardef@1ae620forg.highwire.dtl.DTLVardef@1a7df3dorg.highwire.dtl.DTLVardef@314fe1_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2021

Alzheimer's disease BIN1 coding variants increase intracellular Aβ by interfering with BACE1 recycling

Genetics identified BIN1 as the second most important risk locus associated with late-onset Alzheimers disease, after APOE4. Here we show the consequences of two coding variants in BIN1 (rs754834233 and rs138047593), both in terms of intracellular beta-amyloid accumulation (iAbeta) and early endosome enlargement, two interrelated early cytopathological Alzheimers disease phenotypes, supporting their association with LOAD risk. We previously found that Bin1 deficiency potentiates beta-amyloid production by decreasing BACE1 recycling and enlarging early endosomes. Here, we demonstrate that the expression of the two LOAD mutant forms of Bin1 did not rescue the iAbeta accumulation and early endosome enlargement induced by Bin1 knockdown and recovered by wild-type Bin1. The LOAD coding variants reduced Bin1 interaction with BACE1 likely causing a dominant-negative effect since Bin1 mutants, but not wild-type Bin1, overexpression increased iAbeta42 due to defective BACE1 recycling and accumulation in early endosomes. Endocytic recycling of transferrin was similarly affected by Bin1 wild-type and mutants, indicating that Bin1 is a general regulator of endocytic recycling. These data show that the LOAD mutations in Bin1 lead to a loss of function, suggesting that endocytic recycling defects are an early causal mechanism of Alzheimers disease.

neuroscience↗

bioRxiv2019

Neuronal aging potentiates beta-amyloid generation via amyloid precursor protein endocytosis

Aging increases the risk of Alzheimers disease (AD). During normal aging synapses decline and {beta}-Amyloid (A{beta}) accumulates. An A{beta} defective clearance with aging is postulated as responsible for A{beta} accumulation, although a role for increased A{beta} production with aging can also lead to A{beta} accumulation. To test this hypothesis, we established a long-term culture of primary mouse neurons that mimics neuronal aging (lysosomal lipofuscin accumulation and synapse decline). Intracellular endogenous A{beta}42 accumulated in aged neurites due to increased amyloid-precursor protein (APP) processing. We show that APP processing is up-regulated by a specific age-dependent increase in APP endocytosis. Endocytosed APP accumulated in early endosomes that, in turn were found augmented in aged neurites. APP processing and early endosomes up-regulation was recapitulated in vivo. Finally, we found that inhibition of A{beta} production reduced the decline in synapses in aged neurons. We propose that potentiation of APP endocytosis by neuronal aging increases A{beta} production, which contributes to aging-dependent decline in synapses.\n\nSummaryHow aging increases the risk of Alzheimers disease is not clear. We show that normal neuronal aging increases the intracellular production of {beta}-amyloid, due to an upregulation of the amyloid precursor protein endocytosis. Importantly, increased A{beta} production contributes to the aging-dependent synapse loss.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=76 SRC=\"FIGDIR/small/616540v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (16K):\norg.highwire.dtl.DTLVardef@1f124e1org.highwire.dtl.DTLVardef@ac34e0org.highwire.dtl.DTLVardef@1c37a2aorg.highwire.dtl.DTLVardef@898e91_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗