Biology subjects

Torres Aleman, I.

Publications and source records attributed to Torres Aleman, I..

10 recordsLinked to original sources

bioRxiv2026

COGNITIVE DETERIORATION IS REVERSED BY AN INSULIN-LIKE GROWTH FACTOR 1 SENSITIZER IN A MOUSE MODEL OF ALZHEIMER DISEASE

Previous observations in preclinical and clinical studies indicate a beneficial effect of insulin-like growth factor 1 (IGF-1) in different neurological illnesses, including Alzheimers disease (AD). AD is the most important neurodegenerative disease in the world and despite previous intensive research and the recent approval of putative disease-modifying therapies, available treatments provide only modest clinical benefit and do not halt disease progression. Consequently, there remains a pressing need to develop novel therapeutic strategies for AD. Since resistance to IGF-1 may be involved in development of AD, as it regulates cognition and amyloid {beta} (A{beta}) metabolism, we recently developed a small molecule IGF-1 sensitizer, AIK3a305, that crosses the blood brain barrier (BBB) and exerts modulatory actions in the brain. Using a mouse model of familial AD, the APP/PS1 mouse, we administered them AIK3a305 for 3 months. Treatment started at 12 months of age, when the disease is already well established, and cognitive deterioration readily measurable. One month after starting daily intraperitoneal injections of AIK3a305, mice showed normal cognitive performance in the Y maze, a measure of working memory that enables daily life activities. After 3 months, cognition remained fully preserved, mood-associated disturbances such as anxiety, were corrected, and brain A{beta} levels significantly ameliorated. AIK3a305 may therefore be a promising novel therapeutic strategy for AD patients.

neuroscience↗

bioRxiv2026

THERAPEUTIC EFFECTS OF AN INSULIN-LIKE GROWTH FACTOR I SENSITIZER IN TRAUMATIC BRAIN INJURY

Traumatic brain injury (TBI) is a condition of high incidence worldwide, but remains mostly undertreated. Previous observations in preclinical studies pointed to a beneficial effect of insulin-like growth factor 1 (IGF-1) in TBI. As brain injury is associated to loss of IGF-1 sensitivity, we tested the therapeutic potential of AIK3a305 (AIK3), a novel IGF-1 sensitizer. Twenty-four hours after mild TBI induced by controlled impact, mice received daily intraperitoneal injections of AIK3 during 4 weeks. We found that TBI-associated sensorimotor disturbances measured with the adhesive-removal test were reverted by AIK3 treatment. In addition, neurological and cognitive disturbances measured by the neurological severity score and Y maze respectively, were also ameliorated by treatment with the IGF-1 sensitizer, whereas increased anxiety after mild TBI was also normalized by AIK3. Circulating levels of IGF-1 were increased after AIK3 treatment in TBI mice, while serum IL-6 levels, a biomarker of inflammation associated to TBI were similar to control mice treated with AIK3. Transcriptomic analysis determined that treatment with AIK3 widely affected gene expression in TBI brains, showing a general reduction in both up- and down-regulated genes. Collectively, these data support the use of IGF-1 sensitizers such as AIK3 for treatment of TBI.

neuroscience↗

bioRxiv2025

INFLUENCE OF LIFESTYLE ON BRAIN SENSITIVITY TO CIRCULATING INSULIN-LIKE GROWTH FACTOR 1

Life style conditions such as social relationships and diet impinge on mood homeostasis, a mechanism that becomes dysregulated in high-incidence mental illnesses such as depression or Alzheimers dementia (AD). Since insulin-like growth factor 1 (IGF-1) modulates mood and its blood levels are altered both in AD and in affective disorders, we investigated whether its activity was altered in the brain of mice submitted to isolation or fed with a high-fat diet (HFD). As in humans, both life style conditions increased anxiety and depression-like behavior. Significantly, both life style conditions abrogated neuronal responses to systemic IGF-1. Thus, enhanced neuronal activity in response to intraperitoneal IGF-1, as determined by Ca++ fiber-photometry in the prefrontal cortex, was lost in isolated or HFD-fed mice. However, only the latter had elevated serum IGF-1 levels. These findings suggest that loss of brain IGF-1 input may contribute to mood disturbances observed in lonely and obese subjects. Furthermore, they provide additional insight into the heightened risk of depression and Alzheimers disease associated with these conditions. Importantly, since the reduction of IGF-1 activity in the brain is not consistently mirrored by its serum levels, serum measurements do not reliably reflect brain IGF-1 activity.

neuroscience↗

bioRxiv2023

Bidirectional Modulation Of Synaptic Transmission By Insulin-Like Growth Factor I

Insulin-like growth factor-I (IGF-I) plays a key role in the modulation of synaptic plasticity, and is an essential factor in learning and memory processes. Indeed, we have demonstrated that IGF-IR activation induces long-term potentiation (LTP) of synaptic transmission (LTPIGF-I) both in the barrel cortex, improving object recognition (Noriega-Prieto et al., 2021), and in the prefrontal cortex, facilitating the extinction of conditioned fear (Maglio et al., 2021). However, during aging, IGF-I levels are decreased, and the effect of this decrease in the induction of synaptic plasticity remains unknown. Here we show that the induction of NMDAR-dependent LTP at layer 2/3 PNs of the mouse barrel cortex is favored or prevented by IGF-I (10nM) or IGF-I (7nM), respectively, when IGF-I is applied 1 hour before the induction of Hebbian LTP. Analyzing the cellular basis of this bidirectional control of synaptic plasticity, we observed that while 10nM IGF-I generates LTP (LTPIGF-I) of the post-synaptic potentials (PSPs) by inducing LTD of the inhibitory post-synaptic currents (IPSCs), 7nM IGF-I generates LTD of the PSPs (LTDIGF-I) by inducing LTD of the excitatory post-synaptic currents (EPSCs). This bidirectional effect of IGF-I is supported by the observation of IGF-IR immunoreactivity at both excitatory and inhibitory synapses. Therefore, IGF-I controls the induction of Hebbian NMDAR-dependent plasticity depending on its concentration, revealing novel cellular mechanisms of IGF-I on synaptic plasticity and in the learning and memory machinery of the brain. SIGNIFICANCE STATEMENTInsulin-like growth factor-I (IGF-I) signalling plays key regulatory roles in multiple processes of brain physiology, such as learning and memory, and brain pathology, such as Alzheimer disease. Yet, the underlying mechanisms remain largely undefined. Here we demonstrate that IGF-I signalling triggers long-term potentiation (LTP) or long-term depression (LTD) of synaptic transmission at cortical synapses in a concentration dependent manner, thus regulating the induction of Hebbian synaptic plasticity. The present work represents an important conceptual advance in our knowledge of the cellular basis of IGF-I signalling in brain function.

neuroscience↗

bioRxiv2023

A Role For Astrocytic Insulin-Like Growth Factor I Receptors In The Response To Ischemic Insult

Increased neurotrophic support, including insulin-like growth factor I (IGF-I), is an important aspect of the adaptive response to ischemic insult. However, recent findings indicate that the IGF-I receptor (IGF-IR) in neurons plays a detrimental role in the response to stroke. Thus, we investigated the role of astrocytic IGF-IR on ischemic insults by deleting it using tamoxifen-regulated Cre deletion in glial fibrillary acidic protein (GFAP) astrocytes, a major cellular component in the response to injury. Ablation of IGF-IR in astrocytes (GFAP-IGF-IR KO mice) resulted in larger ischemic lesions, greater blood-brain-barrier disruption and more deteriorated sensorimotor coordination. RNAseq detetected increases in inflammatory, cell adhesion and angiogenic pathways, while the expression of various classical biomarkers of response to ischemic lesion, including aquaporin 4, complement 1q subunit a, early growth response protein 1, and C-C motif chemokine ligand 2, were significantly increased at the lesion site compared to control littermates. While serum IGF-I levels after injury were decreased in both control and GFAP-IR KO mice, brain IGF-I mRNA expression show larger increases in the latter. Further, greater damage was also accompanied by altered glial reactivity as reflected by changes in the morphology of GFAP astrocytes, and relative abundance of ionized calcium binding adaptor molecule 1 microglia. These results suggest a protective role for astrocytic IGF-IR in the response to ischemic injury.

neuroscience↗

bioRxiv2021

INSULIN-LIKE GROWTH FACTOR I SENSITIZATION REJUVENATES SLEEP PATTERNS IN OLD MICE

Sleep disturbances are common during aging. Compared to young animals, old mice show altered sleep structure, with changes in both slow and fast electrocorticographic (ECoG) activity and fewer transitions between sleep and wake stages. Insulin-like growth factor I (IGF-I), which is involved in adaptive changes during aging, was previously shown to increase ECoG activity in young mice and monkeys. Furthermore, IGF-I shapes sleep architecture by modulating the activity of mouse orexin neurons in the lateral hypothalamus (LH). We now report that both ECoG stimulation and activation of orexin neurons by systemic IGF-I is abrogated in old mice. Moreover, stimulation of orthodromically activated LH neurons by either systemic or local IGF-I in young mice is absent in old mice. As orexin neurons of old mice show markedly increased IGF-I receptor (IGF-IR) levels, suggesting loss of sensitivity to IGF-I, we treated old mice with AIK3a305, a novel IGF-IR sensitizer, and observed restored responses to IGF-I and rejuvenation of sleep patterns. Thus, disturbed sleep structure in aging mice may be related to impaired IGF-I signaling onto orexin neurons, reflecting a broader loss of IGF-I activity in the aged mouse brain.

neuroscience↗

bioRxiv2021

Insulin-Like Growth Factor I Couples Metabolism With Circadian Activity Through Hypothalamic Orexin Neurons

Uncoupling of metabolism and circadian activity is associated with an increased risk of various pathologies, including neurodegeneration. Recently, insulin and the closely related insulin-like growth factor I (IGF-I) were shown to entrain feeding patterns with circadian rhythms. Moreover, both hormones act centrally to modulate peripheral glucose metabolism; however, whereas central targets of insulin actions are intensely scrutinized, those mediating the actions of IGF-I remain undefined. We analyzed whether IGF-I targets orexin neurons in the lateral hypothalamus, as these neurons are involved in circadian rhythms and energy allocation, and are modulated by IGF-I. Mice with disrupted IGF-IR activity in orexin neurons show phase shifts in circadian feeding behavior, loss of circadian orexin expression, and gradually develop sex-dependent metabolic alterations. In addition, modulation by IGF-I of hepatic KLF transcription factors involved in peripheral glucose metabolism is mediated by orexin neurons. Thus, IGF-I entrains energy metabolism and circadian rhythms through hypothalamic orexin neurons.

neuroscience↗

bioRxiv2020

Insulin-Like Growth Factor I Modulates Sleep Through Hypothalamic Orexin Neurons

Although metabolic and sleep disturbances are commonly associated, the underlying processes are not yet fully defined. Insulin-like growth factor-I (IGF-I), an anabolic hormone that shows a circadian pattern in the circulation and activity-dependent entrance in the brain, is associated to sleep regulation along evolution. However, its role in this universal homeostatic process remains poorly understood. We now report that the activity of orexin neurons, a discrete cell population in the lateral hypothalamus that is involved in the circadian sleep/wake cycle and arousal, is modulated by circulating IGF-I. Furthermore, mice with blunted IGF-I receptor activity in orexin neurons have lower levels of orexin in the hypothalamus, show altered electrocorticographic patterns with predominant slow wave activity, reduced onset-sleep latency, and less transitions between sleep and awake stages. Collectively, these results extend the role of this pleiotropic growth factor to shaping sleep architecture through regulation of orexin neurons. We speculate that poor sleep quality associated to diverse conditions may be related to disturbed brain IGF-I input to orexin neurons.

neuroscience↗

bioRxiv2020

INSULIN-LIKE GROWTH FACTOR I MODULATES VULNERABILITY TO STRESS THROUGH OREXIN NEURONS

Knowledge of mechanisms involved in vulnerability/resilience to stress disorders is crucial for prevention and treatment schemes. We previously documented that insulin-like growth factor I (IGF-I) is associated to vulnerability to stress both in mice and humans. Since hypothalamic orexin neurons express IGF-I receptors and are involved in responses to stress, we analyzed their role in the modulatory actions of IGF-I on stress. Anxiolytic actions of IGF-I after exposure to a predator were absent in mice lacking IGF-I receptors in orexin neurons (Firoc mice). Based on these observations we speculated that Firoc mice may be prone to develop fear-related disturbances, including post-traumatic stress disorder (PTSD)-like symptoms when confronted to fear learning, a process that is postulated to be altered in PTSD. Firoc mice submitted to fear conditioning showed increased freezing responses, suggesting aberrant fear learning. Exaggerated freezing was accompanied by increased levels of orexin, together with enhanced c-fos staining of these neurons -an indicator of increased cell activity, and of noradrenergic neurons of the locus coeruleus nucleus, a region downstream of orexinergic activation. After fear conditioning, Firoc mice developed PTSD-like behavioral traits such as prolonged context-dependent fear and post-stress anhedonia. Since abnormal fear learning was ameliorated by chemogenetic (DREADD) inhibition of orexin neurons, reduced IGF-I input to orexin neurons in Firoc mice seems to enhance their excitability to fear-related inputs. Collectively, these results suggest that IGF-I input to orexin neurons is an important determinant of vulnerability to stress disorders, which provides additional targets for therapy of these high social impact conditions.

neuroscience↗

bioRxiv2019

The Insulin Receptor In Astrocytes Is Involved In The Entrance Of Circulating Insulin Into The Brain

Circulating insulin enters into the brain through mechanisms that are not yet entirely understood. We now report that mice lacking insulin receptors (IR) in astrocytes show reduced uptake of circulating insulin and blunted brain responses to this circulating hormone, suggesting that astrocytes form part of the cellular pathway in the entrance of circulating insulin into the brain. Since we previously showed that ablation of IR in astrocytes decreases brain glucose uptake, we conclude that astrocytic IRs regulate uptake of circulating glucose and insulin.

neuroscience↗