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21 pages, 9481 KiB

Open AccessArticle

Postnatal Maturation of the Blood–Brain Barrier in Senescence-Accelerated OXYS Rats, Which Are Prone to an Alzheimer’s Disease-like Pathology

by Ekaterina Rudnitskaya, Tatiana Kozlova, Alena Burnyasheva, Daniil Peunov, Michail Tyumentsev, Natalia Stefanova and Nataliya Kolosova

Int. J. Mol. Sci. 2023, 24(21), 15649; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms242115649 - 27 Oct 2023

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Abstract

Alzheimer’s disease (AD) is an old-age neurodegenerative disorder; however, AD predisposition may arise early in life. Vascular dysfunction makes a big contribution to AD development. Nonetheless, the possible role of early-life vascular dysfunction in AD development is still poorly investigated. Here, using OXYS [...] Read more.

Alzheimer’s disease (AD) is an old-age neurodegenerative disorder; however, AD predisposition may arise early in life. Vascular dysfunction makes a big contribution to AD development. Nonetheless, the possible role of early-life vascular dysfunction in AD development is still poorly investigated. Here, using OXYS rats as a suitable model of the most common (sporadic) type of AD, we investigated maturation of the blood–brain barrier (BBB) in the hippocampus and frontal cortex in the first 3 weeks of life. Using RNA-Seq data, we found an altered expression of BBB-associated genes in the middle of the first and second weeks of life in OXYS rats compared to control rats (Wistar strain). Moreover, by immunohistochemistry and electronic microscopy, we revealed a delay of vascularization and of subsequent pericyte coating of blood vessels in OXYS rats. These specific features were accompanied by an accelerated decrease in BBB permeability estimated using Evans blue dye. Notably, almost all of the observed differences from Wistar rats disappeared on postnatal day 20. Nonetheless, the observed features, which are characteristic of the postnatal period, may have long-term consequences and contribute to neurovascular dysfunction observed in OXYS rats late in life, thereby promoting early development of AD signs. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Brain Disease: Hippocampus as a Nodal Point 2.0)

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17 pages, 6947 KiB

Open AccessArticle

Hyaluronic Acid Conjugated with 17β-Estradiol Effectively Alleviates Estropause-Induced Cognitive Deficits in Rats

by Mu-Hsuan Chen, Hsiao-Chun Lin, Tzu Chao, Viola Szu-Yuan Lee, Chia-Lung Hou, Tsyr-Jiuan Wang and Jeng-Rung Chen

Int. J. Mol. Sci. 2023, 24(21), 15569; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms242115569 - 25 Oct 2023

Cited by 1 | Viewed by 1266

Abstract

Women are at a higher risk of cognitive impairments and Alzheimer’s disease (AD), particularly after the menopause, when the estrous cycle becomes irregular and diminishes. Numerous studies have shown that estrogen deficiency, especially estradiol (E2) deficiency, plays a key role in this phenomenon. [...] Read more.

Women are at a higher risk of cognitive impairments and Alzheimer’s disease (AD), particularly after the menopause, when the estrous cycle becomes irregular and diminishes. Numerous studies have shown that estrogen deficiency, especially estradiol (E2) deficiency, plays a key role in this phenomenon. Recently, a novel polymeric drug, hyaluronic acid–17β-estradiol conjugate (HA-E2), has been introduced for the delivery of E2 to brain tissues. Studies have indicated that HA-E2 crosses the blood–brain barrier (BBB) and facilitates a prolonged E2 release profile while lowering the risk of estrogen-supplement-related side effects. In this study, we used ovariohysterectomy (OHE) rats, a postmenopausal cognitive deficit model, to explore the effect of a 2-week HA-E2 treatment (210 ng/kg body weight, twice a week) on the cholinergic septo-hippocampal innervation system, synaptic transmission in hippocampal pyramidal neurons and cognitive improvements. Our study revealed an 11% rise in choline acetyltransferase (ChAT) expression in both the medial septal nucleus (MS nucleus) and the hippocampus, along with a 14–18% increase in dendritic spine density in hippocampal pyramidal neurons, following HA-E2 treatment in OHE rats. These enhancements prompted the recovery of cognitive functions such as spatial learning and memory. These findings suggest that HA-E2 may prevent and improve estrogen-deficiency-induced cognitive impairment and AD. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Brain Disease: Hippocampus as a Nodal Point 2.0)

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14 pages, 5794 KiB

Open AccessArticle

Effect of Combined Levothyroxine (L-T₄) and 3-Iodothyronamine (T₁AM) Supplementation on Memory and Adult Hippocampal Neurogenesis in a Mouse Model of Hypothyroidism

by Grazia Rutigliano, Andrea Bertolini, Nicoletta Grittani, Sabina Frascarelli, Vittoria Carnicelli, Chiara Ippolito, Stefania Moscato, Letizia Mattii, Claudia Kusmic, Alessandro Saba, Nicola Origlia and Riccardo Zucchi

Int. J. Mol. Sci. 2023, 24(18), 13845; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241813845 - 08 Sep 2023

Cited by 1 | Viewed by 967

Abstract

Mood alterations, anxiety, and cognitive impairments associated with adult-onset hypothyroidism often persist despite replacement treatment. In rodent models of hypothyroidism, replacement does not bring 3-iodothyronamine (T₁AM) brain levels back to normal. T₁AM is a thyroid hormone derivative with cognitive [...] Read more.

Mood alterations, anxiety, and cognitive impairments associated with adult-onset hypothyroidism often persist despite replacement treatment. In rodent models of hypothyroidism, replacement does not bring 3-iodothyronamine (T₁AM) brain levels back to normal. T₁AM is a thyroid hormone derivative with cognitive effects. Using a pharmacological hypothyroid mouse model, we investigated whether augmenting levothyroxine (L-T₄) with T₁AM improves behavioural correlates of depression, anxiety, and memory and has an effect on hippocampal neurogenesis. Hypothyroid mice showed impaired performance in the novel object recognition test as compared to euthyroid mice (discrimination index (DI): 0.02 ± 0.09 vs. 0.29 ± 0.06; t = 2.515, p = 0.02). L-T₄ and L-T₄+T₁AM rescued memory (DI: 0.27 ± 0.08 and 0.34 ± 0.08, respectively), while T₁AM had no effect (DI: −0.01 ± 0.10). Hypothyroidism reduced the number of neuroprogenitors in hippocampal neurogenic niches by 20%. L-T₄ rescued the number of neuroprogenitors (mean diff = 106.9 ± 21.40, t = 4.99, p_corr = 0.003), while L-T₄+T₁AM produced a 30.61% rebound relative to euthyroid state (mean diff = 141.6 ± 31.91, t = 4.44, p_corr = 0.004). We performed qPCR analysis of 88 genes involved in neurotrophic signalling pathways and found an effect of treatment on the expression of Ngf, Kdr, Kit, L1cam, Ntf3, Mapk3, and Neurog2. Our data confirm that L-T₄ is necessary and sufficient for recovering memory and hippocampal neurogenesis deficits associated with hypothyroidism, while we found no evidence to support the role of non-canonical TH signalling. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Brain Disease: Hippocampus as a Nodal Point 2.0)

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15 pages, 7664 KiB

Open AccessArticle

Febrile Seizures Cause a Rapid Depletion of Calcium-Permeable AMPA Receptors at the Synapses of Principal Neurons in the Entorhinal Cortex and Hippocampus of the Rat

by Tatyana Y. Postnikova, Alexandra V. Griflyuk, Arseniy S. Zhigulin, Elena B. Soboleva, Oleg I. Barygin, Dmitry V. Amakhin and Aleksey V. Zaitsev

Int. J. Mol. Sci. 2023, 24(16), 12621; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241612621 - 09 Aug 2023

Cited by 2 | Viewed by 890

Abstract

Febrile seizures (FSs) are a relatively common early-life condition that can cause CNS developmental disorders, but the specific mechanisms of action of FS are poorly understood. In this work, we used hyperthermia-induced FS in 10-day-old rats. We demonstrated that the efficiency of glutamatergic [...] Read more.

Febrile seizures (FSs) are a relatively common early-life condition that can cause CNS developmental disorders, but the specific mechanisms of action of FS are poorly understood. In this work, we used hyperthermia-induced FS in 10-day-old rats. We demonstrated that the efficiency of glutamatergic synaptic transmission decreased rapidly after FS by recording local field potentials. This effect was transient, and after two days there were no differences between control and post-FS groups. During early ontogeny, the proportion of calcium-permeable (CP)-AMPA receptors in the synapses of the principal cortical and hippocampal neurons is high. Therefore, rapid internalization of CP-AMPA receptors may be one of the mechanisms underlying this phenomenon. Using the whole-cell patch-clamp method and the selective CP-AMPA receptor blocker IEM-1460, we tested whether the proportion of CP-AMPA receptors changed. We have demonstrated that FS rapidly reduces synaptic CP-AMPA receptors in both the hippocampus and the entorhinal cortex. This process was accompanied by a sharp decrease in the calcium permeability of the membrane of principal neurons, which we revealed in experiments with kainate-induced cobalt uptake. Our experiments show that FSs cause rapid changes in the function of the glutamatergic system, which may have compensatory effects that prevent excessive excitotoxicity and neuronal death. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Brain Disease: Hippocampus as a Nodal Point 2.0)

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16 pages, 4568 KiB

Open AccessArticle

Ambiguous Contribution of Glucocorticosteroids to Acute Neuroinflammation in the Hippocampus of Rat

by Liya V. Tret’yakova, Alexey A. Kvichansky, Ekaterina S. Barkovskaya, Anna O. Manolova, Alexey P. Bolshakov and Natalia V. Gulyaeva

Int. J. Mol. Sci. 2023, 24(13), 11147; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241311147 - 06 Jul 2023

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Abstract

Effects of modulation of glucocorticoid and mineralocorticoid receptors (GR and MR, respectively) on acute neuroinflammatory response were studied in the dorsal (DH) and ventral (VH) parts of the hippocampus of male Wistar rats. Local neuroinflammatory response was induced by administration of bacterial lipopolysaccharide [...] Read more.

Effects of modulation of glucocorticoid and mineralocorticoid receptors (GR and MR, respectively) on acute neuroinflammatory response were studied in the dorsal (DH) and ventral (VH) parts of the hippocampus of male Wistar rats. Local neuroinflammatory response was induced by administration of bacterial lipopolysaccharide (LPS) to the DH. The modulation of GR and MR was performed by dexamethasone (GR activation), mifepristone, and spironolactone (GR and MR inhibition, respectively). Experimental drugs were delivered to the dentate gyrus of the DH bilaterally by stereotaxic injections. Dexamethasone, mifepristone, and spironolactone were administered either alone (basal conditions) or in combination with LPS (neuroinflammatory conditions). Changes in expression levels of neuroinflammation-related genes and morphology of microglia 3 days after intrahippocampal administration of above substances were assessed. Dexamethasone alone induced a weak proinflammatory response in the hippocampal tissue, while neither mifepristone nor spironolactone showed significant effects. During LPS-induced neuroinflammation, GR activation suppressed expression of selected inflammatory genes, though it did not prevent appearance of activated forms of microglia. In contrast to GR activation, GR or MR inhibition had virtually no influence on LPS-induced inflammatory response. The results suggest glucocorticosteroids ambiguously modulate specific aspects of neuroinflammatory response in the hippocampus of rats at molecular and cellular levels. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Brain Disease: Hippocampus as a Nodal Point 2.0)

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15 pages, 5376 KiB

Open AccessArticle

Acoustic Stress Induces Opposite Proliferative/Transformative Effects in Hippocampal Glia

by Fernando Cruz-Mendoza, Sonia Luquin, Joaquín García-Estrada, David Fernández-Quezada and Fernando Jauregui-Huerta

Int. J. Mol. Sci. 2023, 24(6), 5520; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24065520 - 14 Mar 2023

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Abstract

The hippocampus is a brain region crucially involved in regulating stress responses and highly sensitive to environmental changes, with elevated proliferative and adaptive activity of neurons and glial cells. Despite the prevalence of environmental noise as a stressor, its effects on hippocampal cytoarchitecture [...] Read more.

The hippocampus is a brain region crucially involved in regulating stress responses and highly sensitive to environmental changes, with elevated proliferative and adaptive activity of neurons and glial cells. Despite the prevalence of environmental noise as a stressor, its effects on hippocampal cytoarchitecture remain largely unknown. In this study, we aimed to investigate the impact of acoustic stress on hippocampal proliferation and glial cytoarchitecture in adult male rats, using environmental noise as a stress model. After 21 days of noise exposure, our results showed abnormal cellular proliferation in the hippocampus, with an inverse effect on the proliferation ratios of astrocytes and microglia. Both cell lineages also displayed atrophic morphologies with fewer processes and lower densities in the noise-stressed animals. Our findings suggest that, stress not only affects neurogenesis and neuronal death in the hippocampus, but also the proliferation ratio, cell density, and morphology of glial cells, potentially triggering an inflammatory-like response that compromises their homeostatic and repair functions. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Brain Disease: Hippocampus as a Nodal Point 2.0)

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22 pages, 5906 KiB

Open AccessArticle

Transcriptome Profiling of the Hippocampal Seizure Network Implicates a Role for Wnt Signaling during Epileptogenesis in a Mouse Model of Temporal Lobe Epilepsy

by Muriel D. Mardones and Kunal Gupta

Int. J. Mol. Sci. 2022, 23(19), 12030; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231912030 - 10 Oct 2022

Cited by 7 | Viewed by 2419

Abstract

Mesial temporal lobe epilepsy (mTLE) is a life-threatening condition characterized by recurrent hippocampal seizures. mTLE can develop after exposure to risk factors such as febrile seizure, trauma, and infection. Within the latent period between exposure and onset of epilepsy, pathological remodeling events occur [...] Read more.

Mesial temporal lobe epilepsy (mTLE) is a life-threatening condition characterized by recurrent hippocampal seizures. mTLE can develop after exposure to risk factors such as febrile seizure, trauma, and infection. Within the latent period between exposure and onset of epilepsy, pathological remodeling events occur that contribute to epileptogenesis. The molecular mechanisms responsible are currently unclear. We used the mouse intrahippocampal kainite model of mTLE to investigate transcriptional dysregulation in the ipsilateral and contralateral dentate gyrus (DG), representing the epileptogenic zone (EZ) and peri-ictal zone (PIZ). DG were analyzed after 3, 7, and 14 days by RNA sequencing. In both the EZ and PIZ, transcriptional dysregulation was dynamic over the epileptogenic period with early expression of genes representing cell signaling, migration, and proliferation. Canonical Wnt signaling was upregulated in the EZ and PIZ at 3 days. Expression of inflammatory genes differed between the EZ and PIZ, with early expression after 3 days in the PIZ and delayed expression after 7–14 days in the EZ. This suggests that critical gene changes occur early in the hippocampal seizure network and that Wnt signaling may play a role within the latent epileptogenic period. These findings may help to identify novel therapeutic targets that could prevent epileptogenesis. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Brain Disease: Hippocampus as a Nodal Point 2.0)

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Review

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16 pages, 2292 KiB

Open AccessReview

The Role of Insulin Signaling in Hippocampal-Related Diseases: A Focus on Alzheimer’s Disease

by Qi Liu, Zixu Wang, Jing Cao, Yulan Dong and Yaoxing Chen

Int. J. Mol. Sci. 2022, 23(22), 14417; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232214417 - 20 Nov 2022

Cited by 6 | Viewed by 2189

Abstract

Alzheimer’s disease (AD) is a global concern and has become a major public health event affecting human health. Insulin is a metabolic hormone secreted mainly by the peripheral tissue pancreas. In recent years, more and more evidence has proved that insulin regulates various [...] Read more.

Alzheimer’s disease (AD) is a global concern and has become a major public health event affecting human health. Insulin is a metabolic hormone secreted mainly by the peripheral tissue pancreas. In recent years, more and more evidence has proved that insulin regulates various functions of the brain. The hippocampus, one of the earliest brain regions affected by AD, is widely distributed with insulin receptors. Studies have shown that type 2 diabetes mellitus, characterized by insulin resistance, is closely related to AD, which has drawn extensive attention to the relationship between hippocampal insulin signaling and AD. Therefore, we provide an overview of intranasal insulin administration on memory and its underlying mechanism. We also highlight the molecular link between hippocampal insulin resistance and AD and provide a theoretical basis for finding new therapeutic targets for AD in clinical practice. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Brain Disease: Hippocampus as a Nodal Point 2.0)

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