Biology subjects

Romero-Molina, C.

Publications and source records attributed to Romero-Molina, C..

3 recordsLinked to original sources

bioRxiv2026

Reduced LACTB expression in myeloid cells is associated with elevated succinylcarnitine levels and reduced Alzheimers disease risk.

BackgroundLactamase {beta} (LACTB) is a serine {beta}-lactamase-like mitochondrial enzyme associated with cancer progression, obesity, and lipid metabolism. LACTB is located in an Alzheimers Disease (AD) risk locus and has been associated with AD in a proteomic study. MethodsWe performed Mendelian Randomization (MR) analysis to estimate the association between LACTB expression, succinylcarnitine levels, and AD risk. We generated LACTB knock-down (KD) THP1 macrophages, LACTB knock-out (KO) iPSC-derived microglia and LACTB enzymatically-dead (ED) mice. The impact of LACTB loss-of-function in myeloid cells was characterized via transcriptomics, metabolomics, lipidomics, and functional assays. Finally, human LACTB KO microglia precursors were xenotransplanted into the brains of mice with amyloid pathology to assess in vivo interactions with amyloid plaques. ResultsMR analyses revealed that lower LACTB expression in myeloid cells may lead to reduced AD risk and higher levels of succinylcarnitine, a metabolite associated with AD risk. We identified LACTB as a primary enzyme responsible for succinylcarnitine hydrolysis. Transcriptional and functional studies showed that loss of LACTB enhances OXPHOS, and reduces protein synthesis and triglycerides. LACTB expression was upregulated following interferon or TNF stimulation, and its loss modified efferocytosis- related functions under inflammatory conditions. In vivo, xenotransplanted human LACTB KO microglia exhibited enhanced association with amyloid plaques. ConclusionsOur findings define a previously unrecognized axis linking LACTB and succinylcarnitine to myeloid cell function and AD susceptibility. Given the druggability of LACTB and the potential for succinylcarnitine to serve as a translational biomarker, this enzyme represents a promising therapeutic target for modulation of neuroinflammation in AD.

neuroscience↗

bioRxiv2024

Cytokine-induced reprogramming of human macrophages toward Alzheimer's disease-relevant molecular and cellular phenotypes in vitro

Myeloid cells including brain-resident (microglia) and peripheral macrophages play a crucial role in various pathological conditions, including neurodegenerative disorders like Alzheimers disease (AD). They respond to disruption of tissue homeostasis associated with disease conditions by acquiring various transcriptional and functional states. Experimental investigation of these states is hampered by the lack of tools that enable accessible and robust reprogramming of human macrophages toward Alzheimers disease-relevant molecular and cellular phenotypes in vitro. In this study, we investigated the ability of a cytokine mix, including interleukin-4 (IL4), colony stimulating factor 1 (CSF1/MCSF), interleukin 34 (IL34) and transforming growth factor beta (TGF{beta}), to induce reprogramming of cultured human THP-1 macrophages. Our results indicate this treatment led to significant transcriptomic changes, driving THP-1 macrophages towards a transcriptional state reminiscent of disease-associated microglia (DAM) and lipid-associated macrophages (LAM) collectively referred to as DLAM. Transcriptome profiling revealed gene expression changes related to oxidative phosphorylation, lysosome function, and lipid metabolism. Single-cell RNA sequencing revealed an increased proportion of DLAM clusters in cytokine mix-treated THP-1 macrophages. Functional assays demonstrated alterations in cell motility, phagocytosis, lysosomal activity, and metabolic and energetic profiles. Our findings provide insights into the cytokine-mediated reprogramming of macrophages towards disease-relevant states, highlighting their role in neurodegenerative diseases and potential for therapeutic development.

immunology↗

bioRxiv2024

The PHD3-FOXO3 axis modulates the interferon type I response in microglia aggravating Alzheimer's disease progression

Microglia respond to Alzheimers disease (AD) with a variety of transcriptional responses. However, the regulation of specific transcriptional signatures and the contribution of each individual response to disease progression is only starting to be characterized. We have previously shown that hypoxia via hypoxia inducible factor 1 (HIF1) is a strong regulator of A{beta} plaque-associated microglia (A{beta}AM). Here, we characterize the role of HIF1-mediated transcription of Egln3, encoding for PHD3, in A{beta}AM. We show that oligomeric A{beta} treatment (oA{beta}) in vitro induces the expression of Hif1a and Egln3 in microglia, which correlates with the transcriptional activation of genes involved in the interferon type I signature (IFNS) in a PHD3-dependent manner. Mechanistically, we demonstrate FOXO3 to be an important repressor of IFNS in microglia, whose abundance decreases upon A{beta} presence, and, correspondingly, both in human single-nucleus (sn) and mouse A{beta}AM transcriptomics, FOXO3 DNA binding sites define the IFNS. FOXO3 repression of the IFNS is dependent on PHD3, with our results suggesting a physical interaction between both proteins in vitro. In vivo, loss of PHD3 correlate with abrogation of the IFNS and activation of the disease-associated microglia signature (DAM) in A{beta}AM. Transcriptional changes in microglia associate with increased microglia proximity to A{beta} plaques, augmented phagocytosis of A{beta} by microglia, reduced parenchymal levels of A{beta}, and an increase in small-sized plaques. PHD3 deficiency also reduced the A{beta} plaque-associated neuropathology and rescued behavioural deficits of an AD mouse model. Finally, we also demonstrate that microglial PHD3 overexpression during development in the absence of A{beta} pathology is sufficient to induce the IFNS and to behavioural alterations. Altogether, our data strongly indicate that the PHD3-FOXO3 axis controls the microglial IFNS in a cell autonomous manner, contributing to the progression of AD.

neuroscience↗