Search

This editorial, published in the journal Frontiers in Neuroscience, explores the challenges and advancements in neurodegenerative disease research. It emphasizes the complexity of these diseases, which are influenced by both genetic and environmental factors. The editorial highlights the importance of integrating diverse approaches, such as animal models, bioinformatics, and human neuropathological studies, to gain a better understanding of disease development and to develop effective treatments. The document introduces a collection of articles in the journal that delve into various aspects of neurodegenerative disease research, including ALS, FTLD, Alzheimer's disease, and age-associated neurodegeneration. It emphasizes the significance of cross-disciplinary collaboration in understanding neurodegeneration and improving brain health. The document includes author contributions, funding information, acknowledgments, and a conflict of interest statement, as well as a list of references related to neurodegenerative diseases. It concludes by emphasizing the need for further research and collaboration in this field. [Extracted from the article]

Extracellular vesicles (EVs) are shed from the plasma membrane, but the regulation and function of these EVs remain unclear. We found that oxidative stress induced by H2O2 in Hela cells stimulated filopodia formation and the secretion of EVs. EVs were small (150 nm) and labeled for CD44, indicating that they were derived from filopodia. Filopodia‐derived small EVs (sEVs) were enriched with the sphingolipid ceramide, consistent with increased ceramide in the plasma membrane of filopodia. Ceramide was colocalized with neutral sphingomyelinase 2 (nSMase2) and acid sphingomyelinase (ASM), two sphingomyelinases generating ceramide at the plasma membrane. Inhibition of nSMase2 and ASM prevented oxidative stress‐induced sEV shedding but only nSMase2 inhibition prevented filopodia formation. nSMase2 was S‐palmitoylated and interacted with ASM in filopodia to generate ceramide for sEV shedding. sEVs contained nSMase2 and ASM and decreased the level of these two enzymes in oxidatively stressed Hela cells. A novel metabolic labeling technique for EVs showed that oxidative stress induced secretion of fluorescent sEVs labeled with NBD‐ceramide. NBD‐ceramide‐labeled sEVs transported ceramide to mitochondria, ultimately inducing cell death in a proportion of neuronal (N2a) cells. In conclusion, using Hela cells we provide evidence that oxidative stress induces interaction of nSMase2 and ASM at filopodia, which leads to shedding of ceramide‐rich sEVs that target mitochondria and propagate cell death. [ABSTRACT FROM AUTHOR]

We developed a new method to isolate small extracellular vesicles (sEVs) from male and female wild-type and 5xFAD mouse brains to investigate the sex-specific functions of sEVs in Alzheimer's disease (AD). A mass spectrometric analysis revealed that sEVs contained proteins critical for EV formation and Aβ. ExoView analysis showed that female mice contained more GFAP and Aβ-labeled sEVs, suggesting that a larger proportion of sEVs from the female brain is derived from astrocytes and/or more likely to bind to Aβ. Moreover, sEVs from female brains had more acid sphingomyelinase (ASM) and ceramide, an enzyme and its sphingolipid product important for EV formation and Aβ binding to EVs, respectively. We confirmed the function of ASM in EV formation and Aβ binding using co-labeling and proximity ligation assays, showing that ASM inhibitors prevented complex formation between Aβ and ceramide in primary cultured astrocytes. Finally, our study demonstrated that sEVs from female 5xFAD mice were more neurotoxic than those from males, as determined by impaired mitochondrial function (Seahorse assays) and LDH cytotoxicity assays. Our study suggests that sex-specific sEVs are functionally distinct markers for AD and that ASM is a potential target for AD therapy. [ABSTRACT FROM AUTHOR]

Background: Altered ceramide metabolism is implicated in Alzheimer's disease (AD) progression. Although prior work shows that inhibition of neutral sphingomyelinase (nSMase) 2, a key enzyme responsible for hydrolysis of sphingomyelin to ceramide, reduces exosome secretion, attenuates Aβ pathology, and improves cognitive function, these studies have been limited to in vitro application or short‐term treatments in fast‐progressing models. Method: We employed the slow‐progressing APPNL‐F/NL‐F knock‐in (APP KI) AD mouse model and cell type‐specific exosome reporter CD63‐GFPf/f mice to investigate the impact of chronic long‐term nSmase2 inhibition on in vivo neuron‐derived exosome dynamics, region‐specific Aβ plaque load, and cognitive function. Male and female APPNL‐F/NL‐F‐CD63‐GFPf/+ (APP KI‐CD63) mice were treated daily with the nSmase2 inhibitor, GW4869 (GW; 1.25mg/kg BW; i.p.), or vehicle (VEH, DMSO in saline), from 8 months old (mo.) to 13mo. and from 10 mo. to 18mo. We also analyzed ceramide levels in both APP KI and WT mice. Brain‐derived exosomes of 14mo. APP KI females versus males and age‐ and sex‐matched WT mice were also isolated and quantified. Result: We found significant elevations in multiple ceramide species from somatosensory cortex (SC) samples of 14mo. APP KI mice compared to age‐ and sex‐matched WT controls. We also found a sex‐specific increase in total exosomes in 14mo. APP KI females versus males that was absent in WT mice. Chronic inhibition of nSMase2 by GW4869 leads to significantly suppression of neuronal exosome spreading. Non‐linear regression analyses of size distribution curves showed consistent shifts to smaller plaque sizes in GW‐treated APP KI females, which were accompanied by decreased plaque numbers in each region examined. Conversely, plaque load was largely unaffected by GW treatment in APP KI males. T maze trials to examine spatial working memory revealed a female‐specific reduction in spontaneous alternation rate in APP KI vs. WT mice, which was significantly reversed with GW treatment. Conclusion: Our results demonstrate that chronic nSMase2 inhibition suppresses neuronal exosome spreading in APPNL‐F/NL‐F knock‐in mice and preferentially attenuates Aβ pathology and cognitive dysfunction in females, pointing to a strong contribution of sex‐specific alterations in ceramide metabolism and exosome dynamics to the progression of AD‐like pathology in this model. [ABSTRACT FROM AUTHOR]

During pathogenesis of Alzheimer's disease (AD), mitochondria suffer alterations that lead to low energy production and reactive oxygen species formation. However, the mechanism of impaired mitochondria homeostasis in AD is not fully understood. We hypothesized that abnormal sphingolipid metabolism in mitochondria could be one of the contributing factors to mitochondrial dysfunction. Synaptic and non-synaptic mitochondria were isolated from 5xFAD and wild type (WT) mice at 3 and 7 months using Ficoll gradient ultracentrifugation, and their function was analyzed using Seahorse assay. Additionally, mitochondria were analyzed using mass spectrometry for proteomics and sphingolipidomics analyses. Sphingolipid levels were also determined in synaptic and non-synaptic mitochondria isolated from AD patients and healthy controls. We found that synaptic mitochondria isolated from 3-months old 5xFAD mice manifest diminished oxygen consumption as compared to WT. Consistently, proteomics analysis showed that proteins related to respiratory electron transport and oxidative phosphorylation were altered in 5xFAD mice. When quantifying the main sphingolipids in mitochondria, we found that Cer 18:0, Cer 22:0, and Cer 24:1 were increased already at 3 months in 5xFAD mice. No increase in ceramides was detected in mitochondria isolated from AD patients. However, increased levels of sphingosine were found in both 5xFAD mice and AD patients when compared to respective controls. We report that the regulation of sphingolipids in mitochondria is abnormal at 3 months of age in 5xFAD mice, as indicated by the accumulation of long-chain ceramides, which increases with age. Sphingosine levels are increased in both the mitochondria of 5xFAD mice and AD patients. Our data suggest that the sphingolipid composition is dysregulated in mitochondria early during AD pathogenesis.