To investigate the impact of hyperbaric oxygen therapy (HBOT) on the cognitive function of mice with Alzheimer's disease (AD), while also identifying the cellular pathways associated with autophagy involved in the treatment. Twenty-four APP/PSl double transgenic mice were randomly assigned to either Group A or Group B, while another 24 C57 mice were randomly allocated to Group C or Group D. HBOT was administered to mice in Group B and Group D, and the Morris water maze test was used to assess changes in mice behavior. Histological examination using hematoxylin and eosin staining was conducted to observe pathological alterations in the hippocampus of the mice brain tissue. Polymerase chain reaction (PCR) was employed to analyze autophagy-related gene pathways in the hippocampus of the mice. Following HBOT, mice in Group B exhibited a significant reduction in escape latency and a notable increase in residence time within the target quadrant compared with Group A (P<0.05), as well as Group C and Group D (P<0.01). The hippocampal neurons in Group A and Group B mice exhibited disorganized arrangements, characterized by pyknosis and margination. Conversely, neurons in Group C displayed orderly arrangements, retaining intact structures with round nuclei demonstrating clear nuclear staining and normal morphology. The cellular morphology of mice in Group D remained unaffected. PCR analysis revealed no notable disparity in autophagy-related gene expression between Group A and Group C. However, the expression levels of five genes including Tgfb1, Mapk14, Bid, Atg7, and Akt1, were significantly elevated in Group B compared to Group A. HBOT has the potential to improve the cognitive function in mice modeled with AD. This improvement of cognitive function appears to be mediated by the up-regulation of autophagy-related genes, specifically Tgfb1, Mapk14, Bid, Atg7, and Akt1. These results indicate that HBOT may offer a therapeutic strategy for treating AD by enhancing autophagy mechanisms. Key words Alzheimer's disease, Autophagy, Hyperbaric oxygen, Morris water maze, PCR.
- MeSH
- Alzheimer Disease * therapy metabolism genetics psychology MeSH
- Autophagy * physiology MeSH
- Hippocampus metabolism pathology MeSH
- Hyperbaric Oxygenation * MeSH
- Cognition * physiology MeSH
- Humans MeSH
- Disease Models, Animal MeSH
- Mice, Inbred C57BL * MeSH
- Mice, Transgenic * MeSH
- Mice MeSH
- Signal Transduction * MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Alzheimer's disease (AD), a leading cause of dementia worldwide, is a multifactorial neurodegenerative disorder characterized by amyloid-beta plaques, tauopathy, neuronal loss, neuro-inflammation, brain atrophy, and cognitive deficits. AD manifests as familial early-onset (FAD) with specific gene mutations or sporadic late-onset (LOAD) caused by various genetic and environmental factors. Numerous transgenic rodent models have been developed to understand AD pathology development and progression. The TgF344-AD rat model is a double transgenic model that carries two human gene mutations: APP with the Swedish mutation and PSEN-1 with delta exon 9 mutations. This model exhibits a complete repertoire of AD pathology in an age-dependent manner. This review summarizes multidisciplinary research insights gained from studying TgF344-AD rats in the context of AD pathology. We explore neuropathological findings; electrophysiological assessments revealing disrupted synaptic transmission, reduced spatial coding, network-level dysfunctions, and altered sleep architecture; behavioral studies highlighting impaired spatial memory; alterations in excitatory-inhibitory systems; and molecular and physiological changes in TgF344-AD rats emphasizing their age-related effects. Additionally, the impact of various interventions studied in the model is compiled, underscoring their role in bridging gaps in understanding AD pathogenesis. The TgF344-AD rat model offers significant potential in identifying biomarkers for early detection and therapeutic interventions, providing a robust platform for advancing translational AD research. Key words Alzheimer's disease, Transgenic AD models, TgF344-AD rats, Spatial coding.
- MeSH
- Alzheimer Disease * genetics pathology metabolism MeSH
- Amyloid beta-Protein Precursor genetics metabolism MeSH
- Rats MeSH
- Humans MeSH
- Disease Models, Animal * MeSH
- Brain pathology metabolism MeSH
- Rats, Inbred F344 MeSH
- Rats, Transgenic * MeSH
- Presenilin-1 genetics MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Degenerative effects of nerve tissues are often accompanied by changes in vascularization. In this regard, knowledge about hereditary cerebellar degeneration is limited. In this study, we compared the vascularity of the individual cerebellar components of 3-month-old wild-type mice (n = 8) and Purkinje cell degeneration (pcd) mutant mice, which represent a model of hereditary cerebellar degeneration (n = 8). Systematic random samples of tissue sections were processed, and laminin was immunostained to visualize microvessels. A computer-assisted stereology system was used to quantify microvessel parameters including total number, total length, and associated densities in cerebellar layers. Our results in pcd mice revealed a 45% (p < 0.01) reduction in the total volume of the cerebellum, a 28% (p < 0.05) reduction in the total number of vessels and a lower total length, approaching 50% (p < 0.001), compared to the control mice. In pcd mutants, cerebellar degeneration is accompanied by significant reduction in the microvascular network that is proportional to the cerebellar volume reduction therefore does not change density of in the cerebellar gray matter of pcd mice.
- MeSH
- Microvessels MeSH
- Cerebellum * MeSH
- Mice, Neurologic Mutants MeSH
- Mice, Inbred C57BL MeSH
- Mice MeSH
- Purkinje Cells * physiology MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: Accumulation of tau leads to neuroinflammation and neuronal cell death in tauopathies, including Alzheimer's disease. As the disease progresses, there is a decline in brain energy metabolism. However, the role of tau protein in regulating lipid metabolism remains less characterized and poorly understood. METHODS: We used a transgenic rat model for tauopathy to reveal metabolic alterations induced by neurofibrillary pathology. Transgenic rats express a tau fragment truncated at the N- and C-terminals. For phenotypic profiling, we performed targeted metabolomic and lipidomic analysis of brain tissue, CSF, and plasma, based on the LC-MS platform. To monitor disease progression, we employed samples from transgenic and control rats aged 4, 6, 8, 10, 12, and 14 months. To study neuron-glia interplay in lipidome changes induced by pathological tau we used well well-established multicomponent cell model system. Univariate and multivariate statistical approaches were used for data evaluation. RESULTS: We showed that tau has an important role in the deregulation of lipid metabolism. In the lipidomic study, pathological tau was associated with higher production of lipids participating in protein fibrillization, membrane reorganization, and inflammation. Interestingly, significant changes have been found in the early stages of tauopathy before the formation of high-molecular-weight tau aggregates and neurofibrillary pathology. Increased secretion of pathological tau protein in vivo and in vitro induced upregulated production of phospholipids and sphingolipids and accumulation of lipid droplets in microglia. We also found that this process depended on the amount of extracellular tau. During the later stages of tauopathy, we found a connection between the transition of tau into an insoluble fraction and changes in brain metabolism. CONCLUSION: Our results revealed that lipid metabolism is significantly affected during different stages of tau pathology. Thus, our results demonstrate that the dysregulation of lipid composition by pathological tau disrupts the microenvironment, further contributing to the propagation of pathology.
- MeSH
- Alzheimer Disease * pathology MeSH
- Rats MeSH
- Lipid Metabolism MeSH
- Disease Models, Animal MeSH
- Brain metabolism MeSH
- Mice, Transgenic MeSH
- Mice MeSH
- Neurofibrillary Tangles metabolism MeSH
- Rats, Transgenic MeSH
- tau Proteins genetics metabolism MeSH
- Tauopathies * pathology MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
The aim of the present study was to analyze the location of degenerating neurons in the dorsal (insular) claustrum (DCL, VCL) and the dorsal, intermediate and ventral endopiriform nucleus (DEn, IEn, VEn) in rat pups following lithium-pilocarpine status epilepticus (SE) induced at postnatal days [P]12, 15, 18, 21 and 25. The presence of Fluoro-Jade B-positive neurons was evaluated at 4, 12, 24, 48 h and 1 week later. A small number of degenerated neurons was observed in the CL, as well as in the DEn at P12 and P15. The number of degenerated neurons was increased in the CL as well as in the DEn at P18 and above and was highest at longer survival intervals. The CL at P15 and 18 contained a small or moderate number of degenerated neurons mainly close to the medial and dorsal margins also designated as DCl ("shell") while isolated degenerated neurons were distributed in the VCl ("core"). In P21 and 25, a larger number of degenerated neurons occurred in both subdivisions of the dorsal claustrum. The majority of degenerated neurons in the endopiriform nucleus were found in the intermediate and caudal third of the DEn. A small number of degenerated neurons was dispersed in the whole extent of the DEn with prevalence to its medial margin. Our results indicate that degenerated neurons in the claustrum CL and endopiriform nucleus are distributed mainly in subdivisions originating from the ventral pallium; their distribution correlates with chemoarchitectonics of both nuclei and with their intrinsic and extrinsic connections.
- MeSH
- Claustrum * MeSH
- Rats MeSH
- Cerebral Cortex MeSH
- Neurons MeSH
- Status Epilepticus * MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Studying animal models furthers our understanding of Parkinson's disease (PD) pathophysiology by providing tools to investigate detailed molecular, cellular and circuit functions. Different versions of the neurotoxin-based 6-hydroxydopamine (6-OHDA) model of PD have been widely used in rats. However, these models typically assess the result of extensive and definitive dopaminergic lesions that reflect a late stage of PD, leading to a paucity of studies and a consequential gap of knowledge regarding initial stages, in which early interventions would be possible. Additionally, the better availability of genetic tools increasingly shifts the focus of research from rats to mice, but few mouse PD models are available yet. To address these, we characterize here the behavioral, neuronal and ultrastructural features of a graded-dose unilateral, single-injection, striatal 6-OHDA model in mice, focusing on early-stage changes within the first two weeks of lesion induction. We observed early onset, dose-dependent impairments of overall locomotion without substantial deterioration of motor coordination. In accordance, histological evaluation demonstrated a partial, dose-dependent loss of dopaminergic neurons of substantia nigra pars compacta (SNc). Furthermore, electron microscopic analysis revealed degenerative ultrastructural changes in SNc dopaminergic neurons. Our results show that mild ultrastructural and cellular degradation of dopaminergic neurons of the SNc can lead to certain motor deficits shortly after unilateral striatal lesions, suggesting that a unilateral dose-dependent intrastriatal 6-OHDA lesion protocol can serve as a successful model of the early stages of Parkinson's disease in mice.
- MeSH
- Dopamine metabolism MeSH
- Dopaminergic Neurons metabolism MeSH
- Rats MeSH
- Disease Models, Animal MeSH
- Mice MeSH
- Oxidopamine pharmacology MeSH
- Parkinson Disease * etiology pathology MeSH
- Pars Compacta metabolism MeSH
- Substantia Nigra metabolism MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Corpus callosum (CC) je největší mozková komisura spojující levou a pravou mozkovou hemisféru. Obsahuje axony, které propojují především homotopické kortikální oblasti obou hemisfér. Konvenčním MR zobrazením je CC velmi dobře přehledné a hodnotitelné. Postižení corpus callosum lze rozdělit do tří kategorií - vrozené vady, signálové změny a atrofie. První dvě zmíněné jsou na MR většinou správně rozpoznány a zhodnoceny v popisech. Atrofie CC je naproti tomu často přehlížena a připisována pouze pokročilému věku. Může však být podmíněna celou řadou patologických stavů a reflektovat postižení jak bílé, tak šedé hmoty mozkové. K primárnímu postižení bílé hmoty a atrofii CC vedou patologické stavy podmiňující demyelinizaci a následný úbytek axonů. Atrofie CC může být také sekundárním důsledkem postižení šedé hmoty mozkové, konkrétně neuronů III. korové vrstvy, jejichž zánik je následován walleriánskou degenerací axonů projikujících skrze CC. Jelikož jsou vlákna v CC topograficky uspořádána, zánik neuronů určité korové oblasti koresponduje s úbytkem vláken v příslušném segmentu CC a výsledným obrazem je regionální atrofie CC. Článek si klade za úkol nabídnout širší pohled na problematiku atrofie CC, ukázat její pestrou diferenciální diagnostiku.
Corpus callosum (CC) is the largest brain commissure interconnecting the left and right cerebral hemisphere. It consists of fibers projecting mainly to homotopical cortical regions and is well visualized on the conventional MR scans. The main types of callosal abnormalities are congenital defects, signal changes and atrophy, where the first two are rarely unnoticed and unreported - contrary to atrophy, which is frequently attributed to the old age only. Aside from age-related involution, callosal atrophy may be caused by a broad spectrum of pathological conditions damaging either white or gray matter. Demyelinating conditions lead to CC atrophy by primary damage of white matter. Loss of cortical neurons and subsequent wallerian degeneration lead to loss of axons projecting through CC and its secondary atrophy. Because fibers in CC are topographically arranged, loss of neurons in certain cortical regions corresponds to loss of fibers (and thus loss of volume) in certain segments of CC, resulting in regional callosal atrophy. The aim of this article is to provide a broader view on the atrophy of corpus callosum, present its differential diagnosis and potential practical use.
- MeSH
- Atrophy diagnostic imaging etiology pathology MeSH
- Corpus Callosum * diagnostic imaging pathology MeSH
- Diagnosis, Differential MeSH
- Diffuse Axonal Injury diagnostic imaging classification pathology MeSH
- Humans MeSH
- Magnetic Resonance Imaging MeSH
- Nervous System Diseases * diagnostic imaging classification pathology MeSH
- Neurodegenerative Diseases diagnostic imaging pathology MeSH
- Multiple Sclerosis diagnostic imaging pathology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
In neurodegenerative diseases, changes in neuronal proteins in the cerebrospinal fluid and blood are viewed as potential biomarkers of the primary pathology in the central nervous system (CNS). Recent reports suggest, however, that level of neuronal proteins in fluids also alters in several types of epilepsy in various age groups, including children. With increasing evidence supporting clinical and sub-clinical seizures in Alzheimer's disease, Lewy body dementia, Parkinson's disease, and in other less common neurodegenerative conditions, these findings call into question the specificity of neuronal protein response to neurodegenerative process and urge analysis of the effects of concomitant epilepsy and other comorbidities. In this article, we revisit the evidence for alterations in neuronal proteins in the blood and cerebrospinal fluid associated with epilepsy with and without neurodegenerative diseases. We discuss shared and distinctive characteristics of changes in neuronal markers, review their neurobiological mechanisms, and consider the emerging opportunities and challenges for their future research and diagnostic use.
- MeSH
- Alzheimer Disease * pathology MeSH
- Amyloid beta-Peptides MeSH
- Biomarkers MeSH
- Child MeSH
- Epilepsy * MeSH
- Humans MeSH
- Neurodegenerative Diseases * complications diagnosis MeSH
- tau Proteins MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Publication type
- Journal Article MeSH
Finding a cure for Alzheimer's disease (AD) has been notoriously challenging for many decades. Therefore, the current focus is mainly on prevention, timely intervention, and slowing the progression in the earliest stages. A better understanding of underlying mechanisms at the beginning of the disease could aid in early diagnosis and intervention, including alleviating symptoms or slowing down the disease progression. Changes in social cognition and progressive parvalbumin (PV) interneuron dysfunction are among the earliest observable effects of AD. Various AD rodent models mimic these early alterations, but only a narrow field of study has considered their mutual relationship. In this review, we discuss current knowledge about PV interneuron dysfunction in AD and emphasize their importance in social cognition and memory. Next, we propose oxytocin (OT) as a potent modulator of PV interneurons and as a promising treatment for managing some of the early symptoms. We further discuss the supporting evidence on its beneficial effects on AD-related pathology. Clinical trials have employed the use of OT in various neuropsychiatric diseases with promising results, but little is known about its prospective impacts on AD. On the other hand, the modulatory effects of OT in specific structures and local circuits need to be clarified in future studies. This review highlights the connection between PV interneurons and social cognition impairment in the early stages of AD and considers OT as a promising therapeutic agent for addressing these early deficits.
- MeSH
- Alzheimer Disease * pathology MeSH
- Hippocampus pathology MeSH
- Interneurons MeSH
- Cognition MeSH
- Humans MeSH
- Disease Models, Animal MeSH
- Mice, Transgenic MeSH
- Oxytocin MeSH
- Parvalbumins metabolism MeSH
- Prospective Studies MeSH
- Social Cognition MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
In Alzheimer's disease (AD), two mutually exclusive amino-terminal-dependent conformations have been reported to occur during the aggregation of Tau protein into neurofibrillary tangles (NFTs). An early conformation of full-length Tau, involving the bending of the amino terminus over the third repeated domain, is recognized by the Alz-50 antibody, followed by a second conformation recognized by Tau-66 antibody that depends on the folding of the proline-rich region over the third repeated domain in a molecule partially truncated at the amino- and carboxyl-termini. α-1-antichymotrypsin (ACT) is an acute phase serum glycoprotein that accumulates abnormally in the brain of AD patients, and since it is considered to promote the in vitro and in vivo aggregation of amyloid-β, we here seek further evidence that ACT may also contribute to the abnormal aggregation of Tau in AD. By analyzing brain samples from a population of AD cases under immunofluorescence and high-resolution confocal microscopy, we demonstrate here the abundant expression of ACT in hippocampal neurons, visualized as a granular diffuse accumulation, frequently reaching the nuclear compartment. In a significant number of these neurons, intracellular NFTs composed of abnormally phosphorylated and truncated Tau at Asp421 were also observed to coexist in separated regions of the cytoplasm. However, we found strong colocalization between ACT and diffuse aggregates of Tau-66-positive granules, which was not observed with Alz-50 antibody. These results suggest that ACT may play a role during the development of Tau conformational changes facilitating its aggregation during the formation of the neurofibrillary pathology in AD.
