Biology subjects

Solas, M.

Publications and source records attributed to Solas, M..

4 recordsLinked to original sources

bioRxiv2025

Microglial SIRT2 deficiency aggravates cognitive decline and amyloid pathology in Alzheimer's disease

Sirtuin 2 (SIRT2), a NAD+-dependent deacetylase, has been implicated in aging and neurodegenerative diseases such as Alzheimers disease (AD). While global SIRT2 inhibition has shown promise in reducing amyloid-beta pathology and cognitive deficits in different mouse models of AD, peripheral SIRT2 inhibition has been associated with adverse effects, such as increased inflammation. This suggests that targeted inhibition of specific cellular populations within the brain may represent a more precise and effective approach for the treatment of AD. To explore this hypothesis, we generated a conditional microglial SIRT2 knockout mouse model in the context of AD. Our results reveal that microglial SIRT2 reduction does not confer protective effects in the APP/PS1 model; rather, it aggravates cognitive decline, accelerates amyloid plaque deposition, and increases levels of pro-inflammatory cytokines at early stages of AD pathology. Transcriptomic analysis further indicates that SIRT2-deficient microglia exhibit altered expression of genes associated with aging and synaptic dysfunction. This phenotype was accompanied by increased phagocytosis of synaptic elements and impaired long-term potentiation. These findings suggest that while SIRT2 inhibition in some contexts may be beneficial, targeted inhibition within microglia could accelerate AD progression, underscoring the need for cell-specific approaches when considering SIRT2 as a therapeutic target.

neuroscience↗

bioRxiv2023

Neuropathological stage-dependent proteome mapping of the olfactory tract in Alzheimer's disease: From early olfactory-related omics signatures to computational repurposing of drug candidates

Alzheimers disease (AD) is the most common form of dementia, characterized by an early olfactory dysfunction, progressive memory loss and behavioral deterioration. Albeit substantial progress has been made in characterizing AD-associated molecular and cellular events, there is an unmet clinical need for new therapies. In this work, olfactory tract proteotyping performed in controls and AD subjects (n=17/group) showed a Braak stage-dependent proteostatic impairment accompanied by the progressive modulation of amyloid precursor protein (APP) and tau functional interactomes. To implement a computational repurposing of drug candidates with capacity to reverse early AD-related olfactory omics signatures, we generated a consensual olfactory omics signatures (OMSs) database compiling differential omics datasets obtained by mass-spectrometry or RNA-sequencing derived from initial AD across the olfactory axis. Using the Connectivity Map (CMAP)-based drug repurposing approach, PKC, EGFR, Aurora kinase, Glycogen synthase kinase and CDK inhibitors were the top pharmacologic classes capable to restore multiple OMSs, whereas compounds with targeted activity to inhibit PI3K, IGF-1, microtubules and PLK represented a family of drugs with detrimental potential to induce olfactory AD-associated gene expression changes. In-vitro validation assays revealed that pretreatment of human neuron-like SH-SY5Y cells with the EGFR inhibitor AG-1478 showed a neuroprotective effect against hydrogen peroxide-induced damage while the pretreatment with the Aurora kinase inhibitor Reversine reduced amyloid-beta (A{beta})-induced neurotoxicity. Taken together, our data pointed out that olfactory omics signatures may be useful as substrates for drug repurposing to propose novel neuroprotective treatments against AD. STATEMENTSO_ST_ABSData availability statementC_ST_ABSMass-spectrometry data and search results files were deposited in the Proteome Xchange Consortium via the JPOST partner repository (https://repository.jpostdb.org) with the identifier PXD038061 for ProteomeXchange and JPST001921 for jPOST (for reviewers: https://repository.jpostdb.org/preview/1400199357636bce4231af5 Access key: 8609). The data supporting the findings of this study are available in Supplementary Material. Raw data are available from the corresponding author, upon reasonable request. Funding statementThis work was funded by grants from the Spanish Ministry of Science, Innovation and Universities (Ref. PID2019-110356RB-I00/AEI/10.13039/501100011033) to J.F.-I. and E.S. and the Department of Economic and Business Development from Government of Navarra (Ref. 0011-1411-2023-000028 to E.S.). PC-C was supported by a predoctoral fellowship from the Public University of Navarra (UPNA). ML-M is supported by a postdoctoral fellowship from Miguel Servet Foundation-Navarrabiomed. EA-C is supported by "Programa MRR Investigo 2023" in the framework of the European Union recovery and resilience facility. Conflict of interest disclosureAuthors declare that they have no conflicts of interest/financial disclosures. Ethics approval and patient consent statementAccording to the Spanish Law 14/2007 of Biomedical Research, inform written consent from several Spanish Neurological Tissue Banks was obtained for research purposes from relatives of subjects included in this study. According to the Declaration of Helsinki, all assessments, post-mortem evaluations, and experimental procedures were previously approved by the Clinical Ethics Committee of Navarra Health Service (Study code: PI_2019/108).

neuroscience↗

bioRxiv2022

GLUT1 ablation in astrocytes paradoxically improves central and peripheral glucose metabolism via enhanced insulin-stimulated ATP release

Astrocytes are considered an essential source of blood-borne glucose or its metabolites to neurons. Nonetheless, the necessity of the main astrocyte glucose transporter, i.e. GLUT1, for brain glucose metabolism has not been defined. Unexpectedly, we found that brain glucose metabolism was paradoxically augmented in mice with astrocytic GLUT1 ablation (GLUT11'GFAP mice). These mice also exhibited improved peripheral glucose metabolism especially in obesity, rendering them metabolically healthier. Importantly, GLUT11'GFAP mice did not present cognitive alterations. Mechanistically, we observed that GLUT1-ablated astrocytes exhibited increased insulin receptor-dependent ATP release, and both astrocyte insulin signalling and brain purinergic signalling are essential for improved brain function and systemic glucose metabolism. Collectively, we demonstrate that astrocytic GLUT1 is central to the regulation of brain energetics, yet its ablation triggers a reprogramming of brain metabolism sufficient to sustain energy requirements, peripheral glucose homeostasis and cognitive function.

neuroscience↗

bioRxiv2021

Trimethylamine N-Oxide (TMAO) links peripheral insulin resistance and cognitive deficiencies in a senescence accelerated mouse model

It has been established that ageing is the major risk factor for cognitive deficiency or neurodegenerative diseases such as Alzheimers disease (AD) and it is becoming increasingly evident that insulin resistance is another factor. Biological plausibility for a link between insulin resistance and dementia is relevant for understanding disease etiology, and to form bases for prevention efforts to decrease disease burden. The dysfunction of the insulin signaling system and glucose metabolism has been proposed to be responsible for brain aging. Normal insulin signaling in the brain is required to mediate growth, metabolic functions, and the survival of neurons and glia. Insulin receptors are densely expressed in the olfactory bulb, the cerebral cortex and the hippocampus and regulate neurotransmitter release and receptor recruitment. In normal elderly individuals, reduced glucose tolerance and decreased insulin levels in the aged brain are typically observed. Furthermore, insulin signaling is aberrantly activated in the AD brain, leading to non-responsive insulin receptor signaling. The senescence accelerated mouse (SAMP8) mouse was one of the accelerated senescence strains that spontaneously developed from breeding pairs of the AKR/J series. The SAMP8 mouse develops early learning and memory deficits (between 6 and 8 months) together with other characteristics similar to those seen in Alzheimers disease. The present project proposes the investigation of the missing link between aging, insulin resistance and dementia. Peripheral but not central insulin resistance was found in SAMP8 mice accompanied by cognitive deficiencies. Furthermore, a marked peripheral inflammatory state (i.e. significantly higher adipose tissue TNF- and IL6 levels) were observed in SAMP8 mice, followed by neuroinflammation that could be due to a higher cytokine leaking into the brain across a aging-disrupted BBB. Moreover, aging-induced gut dysbiosis produces higher TMAO that could also contribute to the peripheral and central inflammatory tone as well as to the cognitive deficiencies observed in SAMP8 mice. All those alterations were reversed by DMB, a treatment inhibits the transformation of choline, carnitine and crotonobetaine, decreaseing TMAO levels. The ever-increasing incidence of neurodegenerative diseases not only limits the life quality of the affected individuals and their families but also poses an enormous demand on the societies. Thus, it is instrumental to pursue novel promising approaches to prevent and treat it at the highest possible speed to rapidly translate them to clinical practice. From this point of view, data obtained from this project will be instrumental to validate the principle approach of microbial dysbiosis and increased TMAO secretion as a key link between aging, insulin resistance and dementia. Collectively, the proposed experiments ideally integrate the aim to promote a novel approach to improve the lives of those suffering from cognitive disturbances.

animal behavior and cognition↗