Biology subjects

Ardiles, A. O.

Publications and source records attributed to Ardiles, A. O..

4 recordsLinked to original sources

bioRxiv2026

Optimized AAV to express the unfolded protein response transcription factor XBP1s ameliorates Alzheimer's disease features in mouse models

Proteostasis impairment at the level of the endoplasmic reticulum (ER) is a salient feature of Alzheimers disease (AD). The unfolded protein response (UPR) is the main pathway to cope with ER stress, where the expression of the transcription factor X-Box binding protein 1 (XBP1) is central to establish repair programs. To artificially enforce the adaptive capacity of the UPR in the AD brain, we recently reported the protective effects of overexpressing active XBP1 in the brain using adeno-associated vectors (AAVs) of AD mice, in addition to aged animals. Here we have generated a next generation vector suitable for clinical testing by (i) expressing codon-optimized human XBP1s without artificial tags, (ii) the use of the synapsin promoter to restrict expression to neurons, and (iii) incorporating a novel variant of AAV2 (AAV-TT) with greater biodistribution (here termed Proteostaser-1). Treatment of 5xFAD mice with Proteostaser-1 improved spatial learning and synaptic plasticity, and reduced the deposition of amyloid plaques in the brain. Proteostaser-1 administration also improved cognition in a model of sporadic AD based on the intracerebral injection of amyloid {beta} oligomers. Our results further support the therapeutic potential of the UPR as a strategy to ameliorate AD features and sustain synaptic function.

cell biology↗

bioRxiv2025

Sex-Specific Neurovascular and Cognitive Deficits in Offspring of Preeclampsia

BackgroundOffspring of preeclampsia may develop long-term neurovascular and cognitive impairments, but the underlying mechanisms remain unclear. We investigate sex-specific alterations in brain vascular function and cognition in a murine model of preeclampsia induced by the nitric oxide synthase inhibitor L-NAME. MethodsPregnant mice received L-NAME (gestational day 7 to 19). Offspring were assessed at postnatal day 5 (P5) and in adulthood (4-5 months). Brain vascular development, angiogenesis, perfusion, cold-induced vasoconstriction, and blood-brain barrier (BBB) integrity were assessed in vivo and ex vivo. Offsprings serum was applied to brain endothelial cell cultures to evaluate endothelial activation and barrier function. Adult cognitive performance was evaluated through behavioral tests and hippocampal long-term potentiation (LTP) recordings. ResultsL-NAME offspring (P5) exhibited reduced brain vascular density, decreased tip cell formation, and impaired cold-induced vasoconstriction, most prominently in males. BBB integrity was compromised, with increased permeability and reduced expression of tight junction proteins (claudin-5, ZO-1), again more pronounced in males. Serum from L-NAME offspring induced endothelial activation and barrier dysfunction in vitro. These effects were accompanied by increased brain and systemic levels of hypoxia markers and proinflammatory cytokines (IL-6, TNF-). Adult L-NAME offspring showed cognitive deficits in recognition and spatial memory tasks, with female offspring displaying more pronounced impairments. These behavioral findings paralleled a reduced magnitude and impaired stabilization of hippocampal LTP in females. ConclusionsPrenatal exposure to a preeclampsia-like environment induces persistent, sex-specific neurovascular and cognitive deficits in offspring. These findings underscore the need for long-term neurological follow-up in children born to preeclamptic pregnancies.

physiology↗

bioRxiv2022

The unfolded protein response transcription factor XBP1s ameliorates Alzheimer`s disease by improving synaptic function and proteostasis

Alteration in the buffering capacity of the proteostasis network is an emerging feature of Alzheimers disease (AD), highlighting the occurrence of endoplasmic reticulum (ER) stress. The unfolded protein response (UPR) is the main adaptive pathway to cope with protein folding stress at the ER. Inositol requiring enzyme-1 (IRE1) is an ER-located kinase and endoribonuclease that operates as a central ER stress sensor, enabling the establishment of adaptive and repair programs through the control of the expression of the transcription factor X-Box binding protein 1 (XBP1). A polymorphism in the XBP1 promoter has been suggested as a risk factor for AD. To artificially enforce the adaptive capacity of the UPR in the AD brain, we developed strategies to express the active form of XBP1 in neurons using preclinical models. Overexpression of an active form of XBP1 in the nervous system using transgenic mice significantly reduced the load of amyloid deposits in the cerebral cortex and hippocampus and preserved synaptic and cognitive function. Moreover, local delivery of XBP1 into the hippocampus of an AD mice using adeno-associated vectors improved long-term potentiation, memory performance, and dendritic spine density. Quantitative proteomics of the hippocampus revealed that XBP1 expression corrects a large proportion of the alterations observed in the 5xFAD model, restoring the levels of several synaptic proteins and factors involved in actin cytoskeleton regulation and axonal growth. Our results illustrate the therapeutic potential of targeting UPR-dependent gene expression programs as a strategy to ameliorate AD features and sustain synaptic function.

animal behavior and cognition↗

bioRxiv2021

Long-term Pannexin 1 ablation promotes structural and functional modifications in hippocampal neurons through the regulation of actin cytoskeleton and Rho GTPases activity.

Enhanced activity and overexpression of Pannexin 1 (PANX1) channels contribute to neuronal pathologies, such as epilepsy and Alzheimers disease (AD). In the hippocampus, the PANX1 channels ablation alters glutamatergic neurotransmission, synaptic plasticity, and memory flexibility. Nevertheless, PANX1-knockout (KO) mice still preserve the ability to learn, suggesting that compensatory mechanisms work to stabilize neuronal activity. Here, we show that the absence of PANX1 in the adult brain promotes a series of structural and functional modifications in KO hippocampal synapses, preserving spontaneous activity. Adult CA1 neurons of KO mice exhibit enhanced excitability, complex dendritic branching, spine maturation, and multiple synaptic contacts compared to the WT condition. These modifications seem to rely on the actin-cytoskeleton dynamics as an increase in actin polymerization and an imbalance between Rac1 and RhoA GTPase activity is observed in the absence of PANX1. Our findings highlight a novel interaction between PANX1, actin, and small Rho GTPases that appear to be relevant for synapse maintenance as a long-term compensatory mechanism for PANX1 deficiency.

neuroscience↗