Biology subjects

Garcia-Diaz Barriga, G.

Publications and source records attributed to Garcia-Diaz Barriga, G..

5 recordsLinked to original sources

bioRxiv2026

A brain immune phenotype independent of Alzheimer's Disease associates with amyloid susceptibility and systemic inflammation

Transcriptomic and proteomic studies have consistently demonstrated substantial molecular heterogeneity across patients with Alzheimer's disease (AD) and other neurodegenerative disorders, leading to the proposal of multiple disease subtypes. However, almost all previous studies have focused on heterogeneity within diseased cohorts, whereas comparatively little attention has been paid to the molecular diversity of neurologically healthy individuals. In the present study, we demonstrate that one of the most prominent transcriptomic programs characterized by a strong immune component previously interpreted as an AD-specific immune subtype is in fact a brain phenotype that exists independently of AD yet interacts with AD susceptibility and is selectively associated with amyloid pathology. The transcriptional effect of the immune phenotype exceeds that of AD pathology-induced changes and is accompanied by alterations of brain cellular compositions and a distinct systemic inflammation. Our findings suggest that part of the molecular heterogeneity observed in neurological diseases might arise from pre-existing brain phenotypes rather than representing disease-specific subtypes. These insights support a precision medicine approach for Alzheimer's disease, whereby individuals with an immune phenotype of the brain could be prospectively identified and monitored, enabling the application of targeted preventive strategies before substantial neuropathology and cognitive decline emerge.

neuroscience↗

bioRxiv2026

Characterization and pharmacological modulation of Alzheimers disease-associated human microglial states

Microglia are central mediators of Alzheimers disease (AD) pathogenesis, yet the mechanisms driving disease-associated microglial states and their therapeutic modulation remain poorly understood. Here, we integrated single-nucleus transcriptomic datasets across the AD spectrum and identified disease- and lipid-associated microglia (DLaM) as a major AD-enriched population linked to genetic risk, neuropathology and cognitive decline. To model this state experimentally, we screened AD-relevant perturbations in human induced pluripotent stem cell (hiPSC)-derived microglia and found that ferric ammonium citrate (FAC) reproducibly induced a DLaM-like state characterized by lipid accumulation, lysosomal dysfunction and impaired A{beta} phagocytosis. Using a transcriptomics-based state-reversion screen, we identified LY2090314 as a potent modulator that restored microglial function and induced a distinct lysosomal-metabolic state. These findings establish a framework for transcriptomic disease-state-guided therapeutic discovery in AD.

neuroscience↗

bioRxiv2022

Enteric glia adopt an activated pro-inflammatory state in response to human and bacterial amyloids

Mounting evidence suggests a role for the microbiome-gut-brain axis in amyloid-associated neurodegeneration, but the pathogenic changes induced by amyloids in the gastro-intestinal tract remain elusive. To scrutinize the early response to amyloids of human and bacterial origin, we challenged primary murine myenteric networks with A{beta}1-42 (vs a scrambled version of A{beta}1-42) and curli (vs culture medium), respectively, and performed shotgun RNA sequencing. Both amyloid types induced a transcriptional signature of DNA damage and cell cycle dysregulation. Using in vitro neurosphere-derived cultures and in vivo amyloid injections we found that enteric glia and smooth muscle cells were the most responsive cell types, showing increased proliferation, {gamma}H2AX burden and SOD2 levels after amyloid challenge. Consistent with this activated state, we identified a pro-inflammatory hub in the transcriptional profile of amyloid-stimulated myenteric networks. Enteric glia were the principal source of the associated cytokines, and in vivo, this was accompanied by an influx of immune cells. Together, these results shed new light on the intrinsic vulnerability of ENS cells to both amyloid species and position enteric glial cell activation as an early driver of neurodegenerative disease progression. Significance statementThe increasing socio-economic impact of Alzheimers disease (AD), long sub-clinical disease progression window, and failure of drug candidates demand mechanistic insight into the early stages of disease development. Epidemiological associations and experimental studies in rodents suggest that the gut may be vulnerable to amyloids and mediate their transfer to the brain. However, whether and how amyloids induce local pathology in the gastro-intestinal wall is not known. We identified a pathogenic program that becomes activated in the gastro-intestinal tract after exposure to amyloid {beta} and curli (the main bacterial amyloid), and show that enteric glia are responsible for creating an amyloid-induced pro-inflammatory environment. This insight of an early response in a distant, more accessible organ than the brain, may have important implications for both disease diagnosis and therapy.

neuroscience↗

bioRxiv2020

M2 Cortex-Dorsolateral striatum stimulation reverses motor symptoms and synaptic deficits in Huntington's Disease

Huntingtons disease (HD) is a neurological disorder characterized by motor disturbances. HD pathology is most prominent in the striatum, the central hub of basal ganglia. The cortex is the main striatal afference and progressive cortico-striatal disconnection characterizes HD. We mapped cortico-striatal dysfunction in HD mice to ultimately modulate the activity of selected cortico-striatal circuits to ameliorate motor symptoms and recover synaptic plasticity. Multimodal MRI in vivo suggested prominent functional network deficits in fronto-striatal compared to motor-striatal pathways, which were accompanied by reduced glutamate levels in the striatum of HD mice. Moreover, optogenetically-stimulated glutamate release from fronto-striatal terminals was reduced in HD mice and electrophysiological responses in striatal neurons were blunted. Remarkably, repeated M2 Cortex-dorsolateral striatum optogenetic stimulation normalized motor behavior in HD mice and evoked a sustained increase of synaptic plasticity. Overall, these results reveal that the selective stimulation of fronto-striatal pathways can become an effective therapeutic strategy in HD.

neuroscience↗

bioRxiv2020

Systematic quantification of synapses in primary neuronal culture

A vast set of neurological disorders is associated with impaired synaptic connectivity. Therefore, modulation of synapse formation could have therapeutic relevance. However, the high density and small size of synapses make their quantification a challenging task. To improve the reliability of synapse-oriented drug screens, we evaluated a panel of synapse-targeting antibodies for their labeling specificity on hippocampal and cortical cell cultures using quantitative immunofluorescence microscopy. For those antibodies that passed multiparametric validation, we assessed pairwise colocalization, an often-used readout for established synapses. We found that even when two pan-synaptic markers were used, the overlap was incomplete, and the presence of spurious signals limited the dynamic range. To circumvent this problem, we implemented a proximity ligation-based approach, that only leads to a signal when two pre- and postsynaptic markers are sufficiently close. We demonstrate that this approach can be applied to different synaptic marker combinations and can be successfully used for quantification of synapse density in cultures of different maturity stage in healthy or pathological conditions. Thus, the unbiased analysis of synapse labeling and exploitation of resident protein proximity, allows increasing the sensitivity of synapse quantifications in neuronal culture and therefore represents a valuable extension of the analytical toolset for in vitro synapse screens.

neuroscience↗