Biology subjects

Moran-Losada, P.

Publications and source records attributed to Moran-Losada, P..

10 recordsLinked to original sources

bioRxiv2026

Plasma proteomics reveals divergent sex-specific senescence and bone biology signatures across neurodegenerative diseases

Neurodegenerative diseases are often accompanied by systemic comorbidities, including changes in bone health, but the molecular relationship between neurodegeneration, skeletal decline, and cellular senescence remains poorly understood. In this study, we investigated sex-specific changes in circulating bone- and senescence-related proteins across the spectrum of Alzheimers disease(AD), Lewbody dementia(LB) and Parkinsons disease(PD). Plasma proteomic profiling was performed on samples from 408 participants deeply phenotyped for neurodegenerative diseases, followed by differential protein and pathway analyses. This study reveals sex-dependent alterations in bone and senescence-related circulating proteins in AD-related, PD and LB-related neurodegenerative diseases, providing insights into the complex relationship between neurodegeneration and bone health. Several candidate proteins were also associated with established plasma neurodegeneration biomarkers, particularly pTau181. Pathway analyses revealed shared mitochondrial and metabolic dysfunction across neurodegenerative diseases, with disease-specific features including vesicle trafficking disruption in AD and inflammatory-senescence pathways in LB, plus sex-divergent patterns in inflammatory signaling and bone-related pathways.

neuroscience↗

bioRxiv2026

Blood-brain barrier dysfunction predicts cognitive trajectory after ischemic stroke

Ischemic stroke doubles the risk of dementia.1-4 Stroke severity and location affect cognition early,5,6 but late dementia risk is not related to infarct characteristics, nor is it reduced by preventing additional strokes,3,6,7 and its mechanism is unknown. We identified a plasma proteomic signature of chronic stroke that was consistent with blood-brain barrier (BBB) dysfunction, including a 58% decrease in plasma levels of platelet-derived growth factor B and downregulation of its pathway compared to healthy controls. During 2 years of follow-up, the stroke-specific proteome was accentuated in stroke survivors who subsequently declined in the processing speed/executive function cognitive domain. To test BBB function, we performed dynamic contrast-enhanced MRI 6-9 months after stroke in an additional cohort and found 1.7-fold higher whole brain BBB leakage compared to controls. Finally, we compared autopsy tissue from people with infarcts and dementia at death to those with infarcts and no dementia. Those who died with dementia had dramatic loss of vascular mural cell coverage compared to those without dementia (median 0.7% vs. 27%). Thus, our proteomic, functional, and structural data implicate chronic BBB dysfunction in cognitive decline late after stroke, revealing potential proteomic and imaging biomarkers and, importantly, a novel target for intervention.

neuroscience↗

bioRxiv2025

Spatial and molecular insights into microglial roles in cerebellar aging

Aging induces region-specific functional decline across the brain. The cerebellum, critical for motor coordination and cognitive function, undergoes significant structural and functional changes with age. The molecular mechanisms driving cerebellar aging--particularly the role of cerebellar glia, including microglia--remain poorly understood. Here, we used single-nuclei RNA sequencing (snRNA-seq), microglial bulk RNA-seq, and multiplexed error-robust fluorescence in situ hybridization (MERFISH) to characterize transcriptional changes associated with cellular aging in the mouse cerebellum. We discovered that microglia exhibited the most pronounced age-related changes of all cell types and that their transcriptional signatures pointed to enhanced neuroprotective immune activation and reduced lipid-droplet accumulation compared to hippocampal microglia. Furthermore, cerebellar microglia in aged mice, compared to young mice, were found in closer proximity to granule cells. This relationship was characterized using the newly defined neuron-associated microglia score, which captures proximity-dependent transcriptional changes and suggests a novel microglial responsiveness. These findings underscore the unique adaptations of the cerebellum during aging and its potential resilience to Alzheimers disease (AD) related pathology, providing crucial insight into region-specific mechanisms that may shape disease susceptibility.

neuroscience↗

bioRxiv2025

Multi-tissue transcriptomic aging atlas reveals predictive aging biomarkers in the killifish

Aging is associated with progressive tissue dysfunction, leading to frailty and mortality. Characterizing aging features, such as changes in gene expression and dynamics, shared across tissues or specific to each tissue, is crucial for understanding systemic and local factors contributing to the aging process. We performed RNA-sequencing on 13 tissues at 6 different ages in the African turquoise killifish, the shortest-lived vertebrate that can be raised in captivity. This comprehensive, sex-balanced atlas dataset reveals the varying strength of sex-age interactions across killifish tissues and identifies age-altered biological pathways that are evolutionarily conserved. Demonstrating the utility of this resource, we discovered that the killifish head kidney exhibits a myeloid bias during aging, a phenomenon more pronounced in females than in males. In addition, we developed tissue-specific transcriptomic clocks and identified biomarkers predictive of chronological age. We show the importance of sex-specific clocks for selected tissues and use the tissue clocks to evaluate a dietary intervention in the killifish. Our work provides a comprehensive resource for studying aging dynamics across tissues in the killifish, a powerful vertebrate aging model.

genomics↗

bioRxiv2024

Circulatory proteins shape microglia state and boost phagocytosis

Microglia, the brains immune cells, are highly responsive to their local environment. Given that circulatory proteins can enter the brain, we asked whether microglia are responsive to such proteins. Here, we identify a stable population of microglia specialized to take up circulatory proteins in a region-specific manner under physiological conditions; human hematopoietic stem cell-derived microglia replacing endogenous microglia in chimeric mice show similar regional specialization. Plasma-positive microglia are characterized by prominent expression of genes related to innate immunity and antigen presentation and exhibit high metabolic and phagocytic activity. This activity is dependent, in part, on microglial uptake and accumulation of circulatory Apolipoprotein AI (ApoA-I). Our findings thus identify a new model of communication between brain and periphery through specialized microglia.

neuroscience↗

bioRxiv2023

A TrkB and TrkC partial agonist restores deficits in synaptic function and promotes activity-dependent synaptic and microglial transcriptomic changes in a late-stage Alzheimer's mouse model

IntroductionTrkB and TrkC receptor signaling promotes synaptic plasticity and interacts with pathways affected by amyloid-{beta} (A{beta})-toxicity. Upregulating TrkB/C signaling could reduce Alzheimers disease (AD)-related degenerative signaling, memory loss, and synaptic dysfunction. MethodsPTX-BD10-2 (BD10-2), a small molecule TrkB/C receptor partial agonist, was orally administered to aged London/Swedish-APP mutant mice (APPL/S) and wild-type controls (WT). Effects on memory and hippocampal long-term potentiation (LTP) were assessed using electrophysiology, behavioral studies, immunoblotting, immunofluorescence staining, and RNA-sequencing. ResultsMemory and LTP deficits in APPL/S mice were attenuated by treatment with BD10-2. BD10-2 prevented aberrant AKT, CaMKII, and GLUA1 phosphorylation, and enhanced activity-dependent recruitment of synaptic proteins. BD10-2 also had potentially favorable effects on LTP-dependent complement pathway and synaptic gene transcription. ConclusionsBD10-2 prevented APPL/S/A{beta}-associated memory and LTP deficits, reduced abnormalities in synapse-related signaling and activity-dependent transcription of synaptic genes, and bolstered transcriptional changes associated with microglial immune response.

neuroscience↗

bioRxiv2023

Proteostasis and lysosomal quality control deficits in Alzheimer's disease neurons

Aging is the most prominent risk factor for Alzheimers disease (AD). However, the cellular mechanisms linking neuronal proteostasis decline to the characteristic aberrant protein deposits in AD brains remain elusive. Here, we develop transdifferentiated neurons (tNeurons) from human dermal fibroblasts as a neuronal model that retains aging hallmarks and exhibits AD-linked vulnerabilities. Remarkably, AD tNeurons accumulate proteotoxic deposits, including phospho-Tau and A{beta}, resembling those in AD patient and APP mouse brains. Quantitative tNeuron proteomics identify aging and AD-linked deficits in proteostasis and organelle homeostasis, most notably in endosome-lysosomal components. Lysosomal deficits in aged tNeurons, including constitutive lysosomal damage and ESCRT-mediated lysosomal repair defects, are exacerbated in AD tNeurons and linked to inflammatory cytokine secretion and cell death. Supporting lysosomal deficits centrality in AD, compounds ameliorating lysosomal function reduce A{beta} deposits and cytokine secretion. Thus, the tNeuron model system reveals impaired lysosomal homeostasis as an early event of aging and AD.

cell biology↗

bioRxiv2022

A spatiotemporal map of the aging mouse brain reveals white matter tracts as vulnerable foci

Aging is the key risk factor for cognitive decline, yet the molecular changes underlying brain aging remain poorly understood. Here, we conducted spatiotemporal RNA-seq of the mouse brain, profiling 1,076 samples from 15 regions across 7 ages and 2 rejuvenation interventions. Our analysis identified a brain-wide gene signature of aging in glial cells, which exhibited spatially defined changes in magnitude. By integrating spatial and single-nucleus transcriptomics, we found that glia aging was particularly accelerated in white matter compared to cortical regions, while specialized neuronal populations showed region-specific expression changes. Rejuvenation interventions, including young plasma injection and dietary restriction, exhibited distinct effects on gene expression in specific brain regions. Furthermore, we discovered differential gene expression patterns associated with three human neurodegenerative diseases, highlighting the importance of regional aging as a potential modulator of disease. Our findings identify molecular foci of brain aging, providing a foundation to target age-related cognitive decline.

neuroscience↗

bioRxiv2020

Cortical Organoids Model Early Brain Development Disrupted by 16p11.2 Copy Number Variants in Autism

Reciprocal deletion and duplication of 16p11.2 region is the most common copy number variation (CNV) associated with Autism Spectrum Disorders. We generated cortical organoids from skin fibroblasts of patients with 16p11.2 CNV to investigate impacted neurodevelopmental processes. We show that organoid size recapitulates macrocephaly and microcephaly phenotypes observed in the patients with 16p11.2 deletions and duplications. The CNV has mirror-opposite effect on neuronal maturation, proliferation, and synapse number, in concordance with its effect on brain growth in humans. We demonstrate that 16p11.2 CNV alters the ratio of neurons to neural progenitors in organoids during early neurogenesis, with excess of neurons and depletion of neural progenitors observed in deletions, and mirror phenotypes in duplications. Transcriptomic and proteomic profiling revealed multiple dysregulated pathways, including defects in neuron migration. Inhibition of activity of the small GTPase RhoA rescued migration deficits. This study provides insights into potential neurobiological mechanisms behind the 16p11.2 CNV during neocortical development.

neuroscience↗

bioRxiv2020

Autism-linked Cullin3 germline haploinsufficiency impacts cytoskeletal dynamics and cortical neurogenesis through RhoA signaling

E3-ubiquitin ligase Cullin3 (Cul3) is a high confidence risk gene for Autism Spectrum Disorder (ASD) and Developmental Delay (DD). To investigate how Cul3 mutations impact brain development, we generated haploinsufficient Cul3 mouse model using CRISPR/Cas9 genome engineering. Cul3 mutant mice exhibited social and cognitive deficits and hyperactive behavior. Brain MRI found decreased volume of cortical regions and changes in many other brain regions of Cul3 mutant mice starting from early postnatal development. Spatiotemporal transcriptomic and proteomic profiling of the brain implicated neurogenesis and cytoskeletal defects as key drivers of Cul3 functional impact. Specifically, dendritic growth, filamentous actin puncta, and spontaneous network activity were reduced in Cul3 mutant mice. Inhibition of small GTPase RhoA, a molecular substrate of Cul3 ligase, rescued dendrite length and network activity phenotypes. Our study identified neuronal cytoskeleton and Rho signaling as primary targets of Cul3 mutation during early brain development.

neuroscience↗