Ignacio Torres-Aleman

Ignacio Torres-Aleman
Achucarro Basque Center for Neuroscience

PhD

About

202
Publications
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Introduction
Ignacio Torres-Aleman currently works at Acucarro Basque Center for Neuroscience. Our Project is focused on the body-brain crosstalk through insulin peptides.

Publications

Publications (202)
Article
Background: Pleiotropic actions of insulin and insulin-like growth factor I (IGF-I) in the brain are context- and cell-dependent, but whether this holds for their receptors (insulin receptor (IR) and IGF-I receptor (IGF-IR), respectively), is less clear. Methods: We compared mice lacking IR or IGF-IR in glial fibrillary astrocytic protein (GFAP)-ex...
Article
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...
Article
Full-text available
Uncoupling of metabolism and circadian activity is associated with an increased risk of a wide spectrum of pathologies. Recently, insulin and the closely related insulin-like growth factor I (IGF-I) were shown to entrain feeding patterns with circadian rhythms. Both hormones act centrally to modulate peripheral glucose metabolism; however, whereas...
Article
Full-text available
Maladaptive coping behaviors are probably involved in post-traumatic stress disorders (PTSD), but underlying mechanisms are incompletely understood. We now report that mice lacking functional insulin-like growth factor I (IGF-I) receptors in orexin neurons of the lateral hypothalamus (Firoc mice) are unresponsive to the anxiolytic actions of IGF-I...
Article
Full-text available
Aging is accompanied by a decline in cognition that can be due to a lower IGF-I level. We studied response facilitation induced in primary somatosensory (S1) cortical neurons by repetitive stimulation of whiskers in young and old mice. Layer 2/3 and 5/6 neurons were extracellularly recorded in young (≤ 6 months of age) and old (≥ 20 month of age) a...
Article
Full-text available
Background: It is known that IGF-I facilitates a waking state and modulates sleep architecture through the activation of orexinergic neurons. However, IGF-I may activate other neurons that may facilitate waking states, such as the locus coeruleus and the basal forebrain, orchestrating an intricate role in brain and cortical regulation. The BF is a...
Article
Full-text available
Background: Sleep disturbances are common during aging. Old mice show altered sleep structure, with changes in both slow and fast electro-corticographic (ECG) activity, and less transitions between sleep and wake stages, as compared to young animals. Insulin-like growth factor I (IGF-I), that is involved in hormonal changes during aging, was previ...
Article
Full-text available
It is known that aging is frequently accompanied by a decline in cognition. Furthermore, aging is associated with lower serum IGF-I levels that may contribute to this deterioration. We studied the effect of IGF-I in neurons of the horizontal diagonal band of Broca (HDB) of young (≤6 months old) and old (≥20-month-old) mice to determine if changes i...
Preprint
Full-text available
Brain regulation of bodily functions requires interoceptive feedback signals carrying information about the periphery. As mice with low serum IGF-I levels (LID mice) show reduced spontaneous physical activity, we speculated that body vigor information might be conveyed by circulating IGF-I, a regulator of skeletal muscle and bone mass that enters t...
Article
Insulin-like growth factor-I (IGF-I) signalling plays a key role in learning and memory processes. While the effects of IGF-I on neurons have been studied extensively, the involvement of astrocytes in IGF-I signalling and the consequences on synaptic plasticity and animal behavior remain unknown. We have found that IGF-I induces long-term potentiat...
Preprint
Full-text available
Sleep disturbances are common during aging. Compared to young animals, old mice show altered sleep structure, with changes in both slow and fast lectrocorticographic (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 i...
Preprint
Full-text available
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 m...
Article
Full-text available
Obesity is a risk factor for Alzheimer’s disease (AD), but underlying mechanisms are not clear. We analyzed peripheral clearance of amyloid β (Aβ) in overweight mice because its systemic elimination may impact brain Aβ load, a major landmark of AD pathology. We also analyzed whether circulating insulin-like growth factor I (IGF-I) intervenes in the...
Poster
Full-text available
Aging and dementia are related to sleep and circadian disturbances. These disturbances are attributed to neurodegeneration of brain networks involved in sleep. On the other hand, increasing evidence supports the notion that Alzheimer’s disease (AD), a condition that presents heterogeneous pathological disturbances, including sleep regulation, is al...
Article
Full-text available
Although sleep disturbances are common co-morbidities of metabolic diseases, the underlying processes linking both are not yet fully defined. Changes in the duration of sleep are paralleled by changes in the levels of insulin-like growth factor-I (IGF-I), an anabolic hormone that shows a circadian pattern in the circulation and activity-dependent e...
Preprint
Full-text available
Background Obesity is a risk factor for Alzheimer´s disease (AD), but underlying mechanisms are not clear.Methods We analyzed peripheral clearance of amyloid β (Aβ) in overweight mice because its systemic elimination may impact on brain Aβ load, a major landmark of AD pathology. We also analyzed whether circulating insulin-like growth factor I (IGF...
Preprint
Full-text available
Obesity is a risk factor for Alzheimer disease (AD), but underlying mechanisms are not clear. We analyzed peripheral clearance of amyloid-beta (Abeta) in overweight mice because its systemic elimination may impact on brain Abeta load, a major landmark of AD pathology. Overweight mice showed increased peripheral Abeta clearance by the liver, the maj...
Preprint
Full-text available
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, is associated to sleep regulation along evolution. However, its role in this universal homeostatic process remains poorly...
Preprint
Full-text available
Insulin-like growth factor-I (IGF-I) signaling plays key regulatory roles in multiple processes of brain physiology and pathology. While the direct effects of IGF-I in neurons have been extensively studied, the astrocyte involvement in IGF-I signaling and the consequences on synaptic plasticity and animal behavior remain unknown. Here we show that...
Preprint
Full-text available
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...
Poster
Increasing evidence supports the notion that Alzheimer´s disease (AD), a condition that presents heterogeneous pathology, is also associated with perturbed metabolic function affecting insulin and insulin-like growth factor I (IGF-I). Thus, whether IGF-I is beneficial or detrimental to brain function in general, and to AD in particular, has led to...
Preprint
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 ci...
Article
Abstract: Increasing evidence supports the notion that Alzheimer’s disease (AD), a condition that presents heterogeneous pathological disturbances, is also associated to perturbed metabolic function affecting insulin and insulin-like growth factor I (IGF-I). While impaired insulin activity leading to insulin resistance has been associated to AD, wh...
Article
Full-text available
We recently reported that exercise increases resilience to stress in young female mice. Underlying mechanisms include an interaction of the ovarian hormone estradiol (E2) with insulin-like growth factor I (IGF-I), and an increase in the hippocampal levels of the latter. Since changes in mood regulation during aging may contribute to increasing inci...
Poster
Changes in cerebral blood flow (CBF) and in the expression of angiogenic growth factors are observed in Alzheimer´s disease (AD), but whether these alterations precede or are a consequence of AD is not yet known. We now explore the role of the insulin receptor (IR) in astrocytes because animals lacking these receptors (GFAP-IR KO mice) show reduced...
Article
Full-text available
Individual susceptibility to anxiety disorders after maladaptive responses to stress is not well understood. We now report that while exploring stress responses in mice after traumatic brain injury (TBI), a condition associated to stress susceptibility, we observed that the anxiogenic effects of either TBI or exposure to life-threatening experience...
Article
Full-text available
The search for the cause of Alzheimer’s disease (AD), that affects millions of people worldwide, is currently one of the most important scientific endeavors from a clinical perspective. There are so many mechanisms proposed, and so disparate changes observed, that it is becoming a challenging task to provide a comprehensive view of possible pathoge...
Article
Astrocytes are major players in brain glucose metabolism, supporting neuronal needs on demand through mechanisms that are not yet entirely clear. Understanding glucose metabolism in astrocytes is therefore of great consequence to unveil novel targets and develop new drugs to restore brain energy balance in pathology. Contrary to what has been held...
Article
Full-text available
Age is the main risk factor for Alzheimer´s disease (AD). With an increasingly aging population, development of affordable screening techniques to determine cognitive status will help identify population-at-risk for further follow-up. Because physical exercise is known to modulate cognitive performance, we used it as a functional test of cognitive...
Data
A, Aβ immunostaining of control (WT) and APP/PS1 (AD) show the presence of small deposits (Aβ plaques) only in the latter. B, Time line of experimental procedure for Y maze plus exercise used in the experiments shown in Fig 2. C, Both sedentary (white bars) and exercised (grey bars) wild type mice learn the Y maze task as indicated by increased ent...
Article
In response to injury, the brain produces different neuroprotective molecules, such as insulin-like growth factor I (IGF-I). However, IGF-I is also taken up by the brain from the circulation in response to physiological stimuli. Herein, we analyzed in mice the relative contribution of circulating and locally produced IGF-I to increased brain IGF-I...
Article
Full-text available
Aims/hypothesisType 2 diabetes is likely to be an independent risk factor for hippocampal-based memory dysfunction, although this complication has yet to be investigated in detail. As dysregulated glycometabolism in peripheral tissues is a key symptom of type 2 diabetes, it is hypothesised that diabetes-mediated memory dysfunction is also caused by...
Article
Inherited neurodegenerative diseases such as Friedreich's ataxia (FRDA), produced by deficiency of the mitochondrial chaperone frataxin (Fxn), shows specific neurological deficits involving different subset of neurons even though deficiency of Fxn is ubiquitous. Because astrocytes are involved in neurodegeneration, we analyzed whether they are also...
Article
The role of IGF-1 and its receptor (IGF-1R) in brain pathology is still unclear. Thus, either reduction of IGFIR or treatment with IGF-1, two apparently opposite actions, has proven beneficial in brain diseases such as Alzheimer's dementia. A possible explanation of this discrepancy is that IGF-1 down-regulates brain IGF-1R levels, as previously se...
Chapter
Aging impairs cerebrovascular plasticity and subsequently leads cerebral hypoperfusion, which synergistically accelerates aging-associated cognitive dysfunction and neurodegenerative diseases associated with impaired neuronal plasticity. On the other hand, over two decades of researches have successfully demonstrated that exercise, or higher level...
Article
Full-text available
The role of insulin-like growth factor I (IGF-I) and its receptor (IGF-IR) in brain pathology is still unclear. Thus, either reduction of IGF-IR or treatment with IGF-I, two apparently opposite actions, has proven beneficial in brain diseases such as Alzheimer´s dementia (AD). A possible explanation of this discrepancy is that IGF-I down-regulates...
Article
Brain activity requires a flux of glucose to active regions to sustain increased metabolic demands. Insulin, the main regulator of glucose handling in the body, has been traditionally considered not to intervene in this process. However, we now report that insulin modulates brain glucose metabolism by acting on astrocytes in concert with IGF-I. The...
Article
We report that astrocytic insulin signaling co-regulates hypothalamic glucose sensing and systemic glucose metabolism. Postnatal ablation of insulin receptors (IRs) in glial fibrillary acidic protein (GFAP)-expressing cells affects hypothalamic astrocyte morphology, mitochondrial function, and circuit connectivity. Accordingly, astrocytic IR ablati...
Article
PI3K proteins family have multiple and essential functions in most cellular events. This family is composed of class I, class II and class III PI3Ks, which upstream and downstream elements are not completely elucidated. Previous studies using the broad PI3K inhibitor, LY294002 allowed to propose that PI3 kinase > Akt pathway is a key element in the...
Article
Previous findings indicate that reducing brain insulin-like growth factor I receptor (IGF-IR) activity promotes ample neuroprotection. We now examined a possible action of IGF-IR on brain glucose transport to explain its wide protective activity, as energy availability is crucial for healthy tissue function. Using (18) FGlucose PET we found that sh...
Article
Full-text available
Mood homeostasis present sexually dimorphic traits which may explain sex differences in the incidence of mood disorders. We explored whether diverse behavioral-setting components of mood may be differentially regulated in males and females by exercise, a known modulator of mood. We found that exercise decreases anxiety only in males. Conversely, ex...
Article
Astrocytes actively participate in neuro-inflammatory processes associated to Alzheimer's disease (AD), and other brain pathologies. We recently showed that an astrocyte-specific intracellular signaling pathway involving an interaction of the phosphatase calcineurin with the transcription factor FOXO3 is a major driver in AD-associated pathological...
Article
Full-text available
Disruption of insulin-like growth factor I (IGF-I) signaling is a key step in the development of cancer or neurodegeneration. For example, interference of the pro-survival IGF-I/AKT/FOXO3 pathway by redox activation of the stress kinases P38 and JNK is instrumental in neuronal death by oxidative stress. However, in astrocytes IGF-I retains its prot...
Article
Several decades ago, the observation that Alzheimer's disease (AD) presents early disturbances in brain glucose metabolism prompted the notion of insulin dysregulation in this condition. Since then, abundant epidemiological evidence has associated AD to insulin resistance as in type 2 diabetes mellitus (T2DM). However, because the role of insulin i...
Article
Full-text available
The objective of this clinical open-label trial was to test the safety, tolerability and efficacy of IGF-1 therapy for autosomal dominant cerebellar ataxia (ADCA) patients. A total of 19 molecularly confirmed patients with SCA3, 1 patient with SCA6 and 6 patients with SCA7 completed our study. They were 8 females and 18 males, 28 to 74 years of age...
Article
Full-text available
Friedreich’s ataxia is an autosomal recessive, severely incapacitating disorder. There is little objective evidence regarding FRDA management. Abnormalities in the insulin/insulin-like growth factor 1 (IGF-1) system (IIS) signalling pathway were thought to play a role in the physiopathological processes of various neurodegenerative disorders, inclu...
Article
Full-text available
Oxidative stress is a proposed mechanism in brain aging, making the study of its regulatory processes an important aspect of current neurobiological research. In this regard, the role of the aging regulator insulin-like growth factor I (IGF-I) in brain responses to oxidative stress remains elusive as both beneficial and detrimental actions have bee...
Article
Oxidative stress is a proposed mechanism in brain aging, making the study of its regulatory processes an important aspect of current neurobiological research. In this regard, the role of the aging regulator insulin-like growth factor I (IGF-I) in brain responses to oxidative stress remains elusive as both beneficial and detrimental actions have bee...
Article
Full-text available
Circulating insulin-like growth factor I (IGF-I) enters the brain and promotes clearance of amyloid peptides known to accumulate in Alzheimer's disease (AD) brains. Both patients and mouse models of AD show decreased level of circulating IGF-I enter the brain as evidenced by a lower ratio of cerebrospinal fluid/plasma IGF-I. Importantly, in presymp...
Article
Full-text available
Loss-of-function mutations in the phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome10) contribute to aberrant cell growth in part through upregulation of the mitogenic IGF-1/PI3K/Akt pathway. In turn, this pathway exerts a homeostatic feedback over PTEN. Using mutagenesis analysis to explore a possible impact of this mutual con...
Article
While increasing evidence demonstrates that physical exercise promotes brain health, little is known on how the reduction of physical activity affects brain function. We investigated whether the cessation of wheel running alters anxiety-like and depression-like behaviors and its impact on adult hippocampal neurogenesis in mice. Male C57BL/6 mice (4...
Article
Full-text available
Background Friedreich’s ataxia (FRDA) is a neurodegenerative disease caused by deficiency of the mitochondrial iron chaperone frataxin (Fxn). FRDA has no cure, but disease-modifying strategies to increase frataxin are under study. Because insulin-like growth factor I (IGF-I) has therapeutic effects in various types of cerebellar ataxia and exerts p...
Article
The previously undisputed neuroprotective role of insulin-like growth factor 1 (IGF-1) has been challenged by recent observations in IGF-1 receptor (IGF-1R) defective mutants. As new ligand-dependent and ligand-independent roles for IGF-1R are now emerging, new insights into the biologic role of brain IGF-1R and its connection with serum and brain...
Article
Full-text available
Central and peripheral insulin-like peptides (ILPs), which include insulin, insulin-like growth factor 1 (IGF1) and IGF2, exert many effects in the brain. Through their actions on brain growth and differentiation, ILPs contribute to building circuitries that subserve metabolic and behavioural adaptation to internal and external cues of energy avail...
Article
The influence of insulin-like growth factor I (IGF-I) on the progression of Alzheimer's disease (AD) is discussed controversially. To help clarify the role of this circulating neurotrophic factor in brain amyloidosis, the major pathological trait in AD, we analyzed plaque formation in a mouse model of AD transgenic for human APP and PS1 mutations w...
Article
Whether insulin-like growth factor I (IGF-I) signaling in Alzheimer's disease (AD) is beneficial or detrimental remains controversial. We now show that a competitive regulation by IGF-I of the phosphatase calcineurin in reactive, but not in quiescent astrocytes drives Alzheimer's pathology. Calcineurin de-phosphorylates the transcription factor Fox...
Article
Increasing evidence indicates that physical exercise induces adaptations at the cellular, molecular, and systemic levels that positively affect the brain. Insulin plays important functional roles within the brain that are mediated by insulin-receptor (IR) signaling. In the hippocampus, insulin improves synaptic plasticity, memory formation, and lea...
Article
Peripheral insulin-like growth factor I (IGF-I) function progressively deteriorates with age. However, whereas deterioration of IGF-I function in the aged brain seems probable, it has not been directly addressed yet. Because serum IGF-I can enter into the brain through the cerebrospinal fluid (CSF), we examined this route of entrance in aged mice....
Article
The synthesis of composite nanoparticles consisting of a magnetite core coated with a layer of the hormone insulin growth factor 1 (IGF-1) is described. The adsorption of the hormone in the different formulations is first studied by electrophoretic mobility measurements as a function of pH, ionic strength, and time. Because of the permeable charact...
Article
Spinocerebellar ataxias (SCAs) constitute a group of autosomal dominant neurodegenerative disorders with no current treatment. The insulin/insulin-like growth factor 1 (IGF-1) system (IIS) has been shown to play a role in the neurological dysfunction of SCAs and other polyglutamine disorders. We aimed to study the biomarker profile of serum IIS com...
Article
Insulin-like growth factors (IGFs) are important modulators of organismal life-span all along phylogeny. These growth factors are widely viewed as detrimental for long life by reducing tissue resistance to oxidative stress. However, IGF-I has been consistently shown to be a potent neuroprotective factor in mammals, and as such, a deterrent of brain...
Chapter
The ancient insulin-like family of peptides gave rise in higher organisms to insulin-growth factors (IGFs) and insulin. Formerly considered functionally divergent, new evidence suggests that IGFs and insulin probably share a close functional relationship. These links are still poorly defined but may eventually turn out to be of great relevance in t...
Article
Upon entry into the central nervous system (CNS), serum insulin-like growth factor-1 (IGF-I) modulates neuronal growth, survival, and excitability. Yet mechanisms that trigger IGF-I entry across the blood-brain barrier remain unclear. We show that neuronal activity elicited by electrical, sensory, or behavioral stimulation increases IGF-I input in...
Article
Insulin-like growth factor I (IGF-I) belongs to an ancient family of hormones already present in early invertebrates. The insulin family is well characterized in mammals, although new members have been described recently. Since its characterization over 50 years ago, IGF-I has been considered a peptide mostly involved in the control of body growth...
Article
While physical exercise clearly has beneficial effects on the brain, fomenting neuroprotection as well as promoting neural plasticity and behavioural modifications, the cellular and molecular mechanisms mediating these effects are not yet fully understood. We have analyzed sedentary and exercised animals to examine the effects of activity on behavi...
Article
Full-text available
Reduced brain input of serum insulin-like growth factor I (IGF-I), a potent neurotrophic peptide, may be associated with neurodegenerative processes. Thus, analysis of the mechanisms involved in passage of blood-borne IGF-I into the brain may shed light onto pathological mechanisms in neurodegeneration and provide new drug targets. A site of entran...