Biology subjects

Serrano, P. A.

Publications and source records attributed to Serrano, P. A..

6 recordsLinked to original sources

bioRxiv2026

Terazosin drives sex-dependent adrenergic-bioenergetic reprogramming to restore network function in Alzheimer's disease

Alzheimers disease (AD) has long been defined by amyloid-{beta} plaques and hyperphosphorylated tau, yet disease-modifying therapies remain critically limited. Growing evidence reframes AD as a system-level failure driven by early dysregulation of synaptic, metabolic, and neuroimmune pathways, preceding overt protein aggregation and originating in selectively vulnerable circuits, including the locus coeruleus (LC)-hippocampal noradrenergic axis. This complexity underscores the need for therapeutic strategies that engage the disease at a network level, early in its trajectory. To this end, using a machine learning-based systems pharmacology framework for drug repurposing applied to human AD transcriptomic datasets, we identified terazosin (TZ) as a candidate predicted to reverse AD-associated molecular signatures. TZ is an FDA-approved -adrenergic receptor antagonist and phosphoglycerate kinase-1 activator. It was administered chronically via the diet (0.5 mg/kg bw/day) to male and female TgF344-AD rats and wild-type littermates from 5 to 11 months of age, preceding overt pathology. Bulk hippocampal RNA sequencing revealed sex-specific transcriptional remodeling in transgenic rats, strongly conserved with human AD datasets. Male TgF344-AD rats exhibited suppression of synaptic and transcriptional maintenance pathways with concurrent activation of metabolic, proteostatic, extracellular matrix, and vascular stress responses; females showed suppression of survival and vascular structural signaling alongside heightened DAM-like immune activation, amyloid-associated stress, and cell death programs. TZ reversed these signatures in a sex-dependent manner: males showed enhanced immune surveillance and reduced proteostasis burden, while females showed reinforcement of synaptic, survival, and metabolic pathways. TgF344-AD rats displayed selective LC-derived hippocampal noradrenergic axonopathy without global neuronal loss. TZ preserved fiber integrity preferentially in females and partially reversed LC vulnerability-associated transcriptional signatures in both sexes. TZ also reduced amyloid-{beta} plaque burden in both sexes, attenuated hyperphosphorylated tau exclusively in females, and induced microglial morphological shifts in males. Finally, TZ restored wild-type spatial learning in transgenic animals, with females appearing to derive the greater cognitive benefit. Together, these findings demonstrate that TZ induced systems-level reprogramming of AD-relevant molecular pathways and preserved vulnerable noradrenergic circuitry in a sex-dependent manner. Moreover, TZ rescued spatial cognition in transgenic rats, with cognitive gains seemingly more pronounced in females. These results support adrenergic-bioenergetic modulation as a translational strategy for early-stage AD and underscore the necessity of sex as a biological variable in disease-modifying treatment development.

neuroscience↗

bioRxiv2026

Agomelatine drives sex-specific neuroprotection and reduced pathology in rat and human Alzheimer's models

Alzheimers disease (AD) remains without effective disease-modifying therapies, underscoring the need for interventions that target interconnected molecular and cellular processes driving cognitive decline. Leveraging a cross-species translational framework integrating a progressive rat model of Alzheimers disease with human iPSC-derived neurons carrying familial AD mutations, we identify agomelatine (AGO) as a disease-modifying candidate. A clinically used melatonergic agonist and 5-HT2C serotonergic antagonist, we found that AGO acts as a sex-selective modulator of AD-related neuronal and microglial dysfunction with therapeutic relevance across species. TgF344-AD rats and their wildtype littermates received chronic dietary AGO ([~]10 mg/kg/day) from 5 to 11 months of age and underwent hippocampal-dependent spatial learning assessment, quantitative hippocampal histopathology, and bulk RNA sequencing to evaluate the therapeutic effect on cognition, pathology, and molecular mechanisms. Human isogenic iPSC-derived cortical neurons carrying PSEN2N141I or APPV717I mutations were treated with 20 {micro}M AGO followed by bulk RNA sequencing, to define AGO-driven transcriptional pathway modulation in AD neurons In TgF344-AD rats, AGO produced robust female-specific benefits. AGO selectively restored hippocampal-dependant cognitive performance in female but not male transgenic rats. These improvements were independent of amyloid burden and instead aligned with reductions in microgliosis and pathogenic AT8-positive tau phosphorylation. Additionally, AGO normalized reactive and amoeboid microglial states exclusively in females and enhanced doublecortin-defined neurogenesis without altering mature NeuN neuronal density. This coordinated hippocampal stabilization highlights AGOs capacity to restore plasticity rather than simply suppress pathology. Transcriptomic analyses revealed sex-divergent mechanisms underlying these effects. In females, AGO activated metabolic, oxygen-handling, lipid-processing, neuroimmune, and CREB/IGF-1 signaling pathways while suppressing ER-stress, epigenetic, and ion-channel transcripts, changes consistent with resilience-promoting cellular reprogramming. In males, AGO preferentially modulated mitochondrial redox biology, transcriptional regulators, and extracellular matrix components. Despite these differences, both sexes showed AGO-induced engagement of conserved AD-relevant pathways, including shared induction of synaptic plasticity and hemoglobin/oxygen-transport related genes, suggesting a convergent neuroprotective molecular signature. To translate these findings to a human system, we examined AGOs effects in PSEN2N141I and APPV717I iPSC-derived cortical neurons. Both mutations produced convergent deficits in synaptic integrity, neuronal maturity, trophic signaling, proteostasis, metabolism, and excitability, alongside dysregulated developmental and ECM-remodeling programs. AGO partially reversed these pathogenic transcriptional changes, up-regulating synaptic, metabolic, vesicle-trafficking, and redox-stress resilience genes while suppressing pathological developmental and inflammatory pathways, demonstrating conserved engagement of neuronal recovery programs. Together, these results identify AGO as a promising non-amyloid therapeutic candidate capable of modulating AD-relevant pathways in rodents and human models. The sex-selective efficacy observed in vivo, combined with conserved transcriptional responses across species, underscores the translational relevance of AGO-driven molecular reprogramming in AD.

neuroscience↗

bioRxiv2023

Histone deacetylase inhibitor RG2833 has therapeutic potential for Alzheimer's disease in females

Nearly two-thirds of patients with Alzheimers are women. Identifying therapeutics specific for women is critical to lowering their elevated risk for developing this major cause of adult dementia. Moreover, targeting epigenetic processes that regulate multiple cellular pathways is advantageous given Alzheimers multifactorial nature. Histone acetylation is an epigenetic process heavily involved in memory consolidation. Its disruption is linked to Alzheimers. Through our computational studies, we predicted that the investigational drug RG2833 (N-[6-(2-aminoanilino)-6-oxohexyl]-4-methylbenzamide) has repurposing potential for Alzheimers. RG2833 is a histone deacetylase HDAC1/3 inhibitor that is orally bioavailable and permeates the blood-brain-barrier. We investigated the RG2833 therapeutic potential in TgF344-AD rats, which are a model of Alzheimers that exhibits age-dependent progression, thus mimicking this aspect of Alzheimers patients that is difficult to establish in animal models. We investigated the RG2833 effects on cognitive performance, gene expression, and AD-like pathology in 11-month TgF344-AD female and male rats. A total of 89 rats were used: wild type n = 45 (17 females, 28 males), and TgF344-AD n = 44 (24 females, 20 males)] across multiple cohorts. No obvious toxicity was detected in the TgF344-AD rats up to 6 months of RG2833-treatment starting at 5 months of age administering the drug in rodent chow at [~]30mg/kg of body weight. We started treatment early in the course of pathology when therapeutic intervention is predicted to be more effective than in later stages of the disease. The drug-treatment significantly mitigated hippocampal-dependent spatial memory deficits in 11-month TgF344-AD females but not in males, compared to wild type littermates. This female sex-specific drug effect has not been previously reported. RG2833-treatment failed to ameliorate amyloid beta accumulation and microgliosis in female and male TgF344-AD rats. However, RNAseq analysis of hippocampal tissue from TgF344-AD rats showed that drug-treatment in females upregulated the expression of immediate early genes, such as Arc, Egr1 and c-Fos, and other genes involved in synaptic plasticity and memory consolidation. Remarkably, out of 17,168 genes analyzed for each sex, no significant changes in gene expression were detected in males at P < 0.05, false discovery rate < 0.05, and fold-change [≥] 1.5. Our data suggest that histone modifying therapeutics such as RG2833 improve cognitive behavior by modulating the expression of immediate early, neuroprotective and synaptic plasticity genes. Our preclinical study supports that RG2833 has therapeutic potential specifically for female Alzheimers patients. RG2833 evaluations using other AD-related models is necessary to confirm our findings.

neuroscience↗

bioRxiv2022

Prostaglandin D2 pathway in a transgenic rat model of Alzheimer's disease: therapeutic potential of timapiprant a DP2 antagonist

The cyclooxygenase pathway, a key mediator of inflammation, is implicated in Alzheimers disease (AD). A deeper investigation is required into the contributions of this pathway to the neuropathology of AD. Cyclooxygenases produce prostaglandins, which have multiple receptors and functions including inflammation, nociception, sleep, cardiovascular maintenance and reproduction. In the brain, prostaglandin D2 (PGD2) is the most abundant prostaglandin, increases the most under pathological conditions, and plays roles in sleep, stroke and inflammation. PGD2 signals through its DP1 and DP2 receptors and their activation can be protective or detrimental. We address the relationship between the PGD2 pathway and AD neuropathology with F344-AD transgenic (Tg-AD) rats that exhibit age-dependent and progressive pathology similar to AD patients. We analyzed the PGD2 pathway in the hippocampus of wild type (WT) rats and their Tg-AD littermates, at the age of 11 months, when Tg-AD rats exhibit plaques and perform significantly worse in hippocampal-dependent cognitive tasks than WT rats. Using mass spectrometry, we determined that PGD2 levels were at least 14.5-fold higher than PGE2, independently of genotype. Immunohistochemistry established that microglial DP1 receptors were more abundant and neuronal DP2 receptors were fewer in Tg-AD than in WT rats. RNA sequencing profiling of 33 genes involved in the PGD2 and PGE2 pathways revealed that mRNA levels were the highest for L-PGDS, the major PGD2 synthase in the brain. To evaluate the pathophysiological significance of our findings on the PGD2 pathway, we treated a subset of rats (WT and Tg-AD males) with timapiprant, a potent and highly selective oral DP2 antagonist being developed as a once-daily oral treatment in patients with allergic inflammation. We conclusively show that timapiprant significantly mitigated some of the AD pathology exhibited by the Tg-AD male rats. More comprehensive studies are necessary to support the therapeutic potential of timapiprant and that of other PGD2-related compounds in the treatment of AD.

neuroscience↗

bioRxiv2022

Females outperform males in spatial learning despite increased amyloid plaques and microgliosis in a TgF344-AD rat model of Alzheimer's disease

Alzheimers disease (AD) is a progressive neurodegenerative disease and is the sixth leading cause of death in the US. AD is more prevalent in females than males. While estrogen provides neuroprotection in females, sex mediated differences in the development of AD pathology are not fully elucidated. Therefore, a comparison of the events that develop between sexes in the early-stage of AD pathology may reveal new potential targets for more effective therapeutic intervention. To address sex differences, we analyzed early stage 9-month male and female TgF344-AD (Tg-AD) rats, an AD model carrying the APPswe and Presenilin 1 (PS1{Delta}E9) mutations that develops progressive age-dependent AD pathology similar to humans. Using active place avoidance (aPAT) tests that assess hippocampal-dependent spatial learning and memory, we found significant deficits in Tg-AD females compared to wild type females, but no significant difference between the two male genotypes. Moreover, significant sex differences were observed in that Tg-AD females outperformed Tg-AD males in several measures of the aPAT test. Unexpectedly, Tg-AD females displayed higher levels of hippocampal amyloid plaques and amoeboid microglia than their Tg-AD male littermates. Furthermore, Tg-AD females experienced less hippocampal neuronal loss and had higher GluA2 subunit levels than Tg-AD males. Based on our findings, we propose that estrogen may protect females against cognitive impairment at early stages of AD by regulating GluA2 levels independently of amyloid plaque deposition and gliosis. Elucidating this potential protective mechanism of action of estrogen in AD could lead to new targets for early intervention.

neuroscience↗

bioRxiv2021

Multi-scale predictive modeling discovers Ibudilast as a polypharmacological agent to improve hippocampal dependent spatial learning and memory and mitigate plaque and tangle pathology in a transgenic rat model of Alzheimer's disease

Alzheimers disease (AD) is a multifactorial disease that exhibits cognitive deficits, neuronal loss, amyloid plaques, neurofibrillary tangles and neuroinflammation in the brain. We developed a multi-scale predictive modeling strategy that integrates machine learning with biophysics and systems pharmacology to model drug actions from molecular interactions to phenotypic responses. We predicted that ibudilast (IBU), a phosphodiesterase inhibitor and toll-like receptor 4 (TLR4) antagonist, inhibited multiple kinases (e.g., IRAK1 and GSG2) as off-targets, modulated multiple AD-associated pathways, and reversed AD molecular phenotypes. We address for the first time the efficacy of ibudilast (IBU) in a transgenic rat model of AD. IBU-treated transgenic rats showed improved cognition and reduced hallmarks of AD pathology. RNA sequencing analyses in the hippocampus showed that IBU affected the expression of pro-inflammatory genes in the TLR signaling pathway. Our results identify IBU as a potential therapeutic to be repurposed for reducing neuroinflammation in AD by targeting TLR signaling.

pharmacology and toxicology↗