Biology subjects

Guimas Almeida, C.

Publications and source records attributed to Guimas Almeida, C..

3 recordsLinked to original sources

bioRxiv2022

Apolipoprotein E intersects with amyloid-β within neurons

Apolipoprotein E4 (ApoE4) is the most important genetic risk factor for Alzheimers disease (AD). Among the earliest changes in AD is endosomal enlargement in neurons, which was reported as enhanced in ApoE4 carriers. ApoE is thought to be internalized into endosomes of neurons, while {beta}-amyloid (A{beta}) accumulates within neuronal endosomes early in AD. However, it remains unknown whether ApoE and A{beta} intersect intracellularly. We show that internalized astrocytic ApoE localizes mostly to lysosomes in neuroblastoma cells and astrocytes, while in neurons it preferentially localizes to endosomes-autophagosomes of neurites. In AD transgenic neurons, astrocyte-derived ApoE intersects intracellularly with amyloid precursor protein (APP)/A{beta}. Moreover, ApoE4 increases the levels of endogenous and internalized A{beta}42 in neurons. Taken together, we demonstrate differential localization of ApoE in neurons, astrocytes and neuron-like cells, and show that internalized ApoE intersects with APP/A{beta} in neurons, which may be of considerable relevance to AD.

neuroscience↗

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

Cholesteryl Hemiazelate Induces Lysosome Dysfunction and Exocytosis in Macrophages

OBJECTIVEA key event in atherogenesis is the formation of lipid-loaded macrophages, lipidotic cells, which exhibit irreversible accumulation of undigested modified low-density lipoproteins in lysosomes. This event culminates with the loss of cell homeostasis, inflammation and cell death. In this study we propose to identify the chemical etiological factors and understanding the molecular and cellular mechanisms responsible for the impairment of lysosome function in macrophages. APPROACH AND RESULTSUsing shotgun lipidomics we have discovered that a family of oxidized lipids (cholesteryl hemiesters, ChE), end products of oxidation of polyunsaturated cholesteryl esters, occurs at higher concentrations in the plasma of two cohorts of cardiovascular disease patients than in the plasma of a control cohort. Macrophages exposed to the most prevalent ChE, cholesteryl hemiazelate (ChA) exhibit lysosome enlargement, peripheral lysosomal positioning, lysosome dysfunction and lipidosis which are irreversible. The transcriptomic profile of macrophages exposed to ChA indicates that the lysosome pathway is deeply affected and is well correlated with lysosome phenotypic and functional changes. Interestingly, the dysfunctional peripheral lysosomes are more prone to fuse with the plasma membrane, secreting their undigested luminal content into the extracellular milieu with potential consequences to the pathology. CONCLUSIONWe identify ChA not only as one of the molecules involved in the etiology of irreversible lysosome dysfunction culminating with lipidosis but also as a promoter of exocytosis of the dysfunctional lysosomes. The latter event is a new mechanism that may be important in the pathogenesis of atherosclerosis.

cell biology↗