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
- Alzheimerova nemoc * genetika patologie metabolismus MeSH
- amyloidový prekurzorový protein beta genetika metabolismus MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- modely nemocí na zvířatech * MeSH
- mozek patologie metabolismus MeSH
- potkani inbrední F344 MeSH
- potkani transgenní * MeSH
- presenilin-1 genetika MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
BACKGROUND: The hippocampal representation of space, formed by the collective activity of populations of place cells, is considered as a substrate of spatial memory. Alzheimer's disease (AD), a widespread severe neurodegenerative condition of multifactorial origin, typically exhibits spatial memory deficits among its early clinical signs before more severe cognitive impacts develop. OBJECTIVE: To investigate mechanisms of spatial memory impairment in a double transgenic rat model of AD. METHODS: In this study, we utilized 9-12-month-old double-transgenic TgF344-AD rats and age-matched controls to analyze the spatial coding properties of CA1 place cells. We characterized the spatial memory representation, assessed cells' spatial information content and direction-specific activity, and compared their population coding in familiar and novel conditions. RESULTS: Our findings revealed that TgF344-AD animals exhibited lower precision in coding, as evidenced by reduced spatial information and larger receptive zones. This impairment was evident in maps representing novel environments. While controls instantly encoded directional context during their initial exposure to a novel environment, transgenics struggled to incorporate this information into the newly developed hippocampal spatial representation. This resulted in impairment in orthogonalization of stored activity patterns, an important feature directly related to episodic memory encoding capacity. CONCLUSIONS: Overall, the results shed light on the nature of impairment at both the single-cell and population levels in the transgenic AD model. In addition to the observed spatial coding inaccuracy, the findings reveal a significantly impaired ability to adaptively modify and refine newly stored hippocampal memory patterns.
- MeSH
- Alzheimerova nemoc * patofyziologie MeSH
- amyloidový prekurzorový protein beta genetika MeSH
- hipokampální oblast CA1 patofyziologie MeSH
- hipokampus patofyziologie MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- modely nemocí na zvířatech * MeSH
- poruchy paměti etiologie patofyziologie MeSH
- potkani inbrední F344 MeSH
- potkani transgenní * MeSH
- prostorová paměť fyziologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Mitochondrial retrograde signaling is a pathway of communication from mitochondria to the nucleus. Recently, natural mitochondrial genome (mtDNA) polymorphisms (haplogroups) received increasing attention in the pathophysiology of human common diseases. However, retrograde effects of mtDNA variants on such traits are difficult to study in humans. The conplastic strains represent key animal models to elucidate regulatory roles of mtDNA haplogroups on defined nuclear genome background. To analyze the relationship between mtDNA variants and cardiometabolic traits, we derived a set of rat conplastic strains (SHR-mtBN, SHR-mtF344 and SHR-mtLEW), harboring all major mtDNA haplotypes present in common inbred strains on the nuclear background of the spontaneously hypertensive rat (SHR). The BN, F344 and LEW mtDNA differ from the SHR in multiple amino acid substitutions in protein coding genes and also in variants of tRNA and rRNA genes. Different mtDNA haplotypes were found to predispose to various sets of cardiometabolic phenotypes which provided evidence for significant retrograde effects of mtDNA in the SHR. In the future, these animals could be used to decipher individual biochemical components involved in the retrograde signaling.
- MeSH
- fenotyp MeSH
- kardiovaskulární nemoci * metabolismus MeSH
- krysa rodu rattus MeSH
- mitochondriální DNA * genetika MeSH
- mitochondrie metabolismus MeSH
- potkani inbrední F344 MeSH
- potkani inbrední SHR MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
AUT00063 and AUT00202 are novel pharmaceutical modulators of the Kv3 subfamily of voltage-gated K+ channels. Kv3.1 channels, which control fast firing of many central auditory neurons, have been shown to decline with age and this may contribute to age-related deficits in central auditory processing. In the present study, the effects of the two novel compounds that specifically modulate Kv3 channels on auditory temporal processing were examined in aged (19-25-month-old) and young-adult (3-5 month-old) Fischer 344 rats (F344) using a behavioral gap-prepulse inhibition (gap-PPI) paradigm. The acoustic startle response (ASR) and its inhibition induced by a gap in noise were measured before and after drug administration. Hearing thresholds in tested rats were evaluated by the auditory brainstem response (ABR). Aged F344 rats had significantly higher ABR thresholds, lower amplitudes of ASR, and weaker gap-PPI compared with young-adult rats. No influence of AUT00063 and AUT00202 administration was observed on ABR hearing thresholds in rats of both age groups. AUT00063 and AUT00202 had suppressive effect on ASR of F344 rats that was more pronounced with AUT00063. The degree of suppression depended on the dose and age of the rats. Both compounds significantly improved the gap-PPI performance in gap detection tests in aged rats. These results indicate that AUT00063 and AUT00202 may influence intrinsic firing properties of neurons in the central auditory system of aged animals and have the potential to treat aged-related hearing disorders.
- MeSH
- akustická stimulace MeSH
- draslíkové kanály Shaw MeSH
- krysa rodu rattus MeSH
- potkani inbrední F344 MeSH
- prepulsní inhibice MeSH
- sluchová percepce * MeSH
- sluchové kmenové evokované potenciály * MeSH
- sluchový práh MeSH
- úleková reakce MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Age-related hearing loss is manifested primarily by a decreased sensitivity to faint sounds, that is, by elevation of the hearing thresholds. Nevertheless, aging also affects the ability of the auditory system to process temporal parameters of the sound stimulus. To explore the precision and reliability of auditory temporal processing during aging, responses to several types of sound stimuli were recorded from neurons of the auditory cortex (AC) of young and aged anaesthetized Fischer 344 rats. In response to broad-band noise bursts, the aged rats exhibited larger response magnitudes, a higher proportion of monotonic units, and also a larger variability of response magnitudes, suggesting a lower stability of the rate code. Of primary interest were the responses to temporally structured stimuli (amplitude-modulated (AM) noise, frequency-modulated (FM) tones, and click trains) recorded separately in the right and left AC. Significant differences of temporal processing were already found between the neuronal responses in the left and right AC in the young animals: for the click trains, the left hemisphere exhibited a greater responsiveness to higher repetition rates, lower vector strength values, and a lower similarity of responses. The two hemispheres were also affected differently by aging. In the right hemisphere, neurons in the aged animals displayed worse synchronization with the AM noise and clicks, but better synchronization with the FM tone. In the left hemisphere, neuronal synchronization with the stimulus modulation improved at a higher age for all three stimuli. The results show that the ability of the aging auditory system to process temporal parameters of the stimulus strongly depends on the stimulus type and on laterality. Furthermore, the commonly reported age-related decline in the temporal processing ability cannot be regarded as general as, at least at the neuronal level in the AC, objective measures of the temporal representation often exhibit age-related improvement instead of deterioration.
BACKGROUND: Microcirculatory factors play an important role in amyloid-β (Aβ)-related neuropathology in Alzheimer's disease (AD). Transgenic (Tg) rat models of mutant Aβ deposition can enhance our understanding of this microvascular pathology. OBJECTIVE: Here we report stereology-based quantification and comparisons (between- and within-group) of microvessel length and number and associated parameters in hippocampal subregions in Tg model of AD in Fischer 344 rats and non-Tg littermates. METHODS: Systematic-random samples of tissue sections were processed and laminin immunostained to visualize microvessels through the entire hippocampus in Tg and non-Tg rats. A computer-assisted stereology system was used to quantify microvessel parameters including total number, total length, and associated densities in dentate gyrus (DG) and cornu ammonis (CA) subregions. RESULTS: Thin hair-like capillaries are common near Aβ plaques in hippocampal subregions of Tg rats. There are a 53% significant increase in average length per capillary across entire hippocampus (p≤0.04) in Tg compared to non-Tg rats; 49% reduction in capillary length in DG (p≤0.02); and, higher microvessel density in principal cell layers (p≤0.03). Furthermore, within-group comparisons confirm Tg but not non-Tg rats have significant increase in number density (p≤0.01) and potential diffusion distance (p≤0.04) of microvessels in principal cell layers of hippocampal subregions. CONCLUSION: We show the Tg deposition of human Aβ mutations in rats disrupts the wild-type microanatomy of hippocampal microvessels. Stereology-based microvascular parameters could promote the development of novel strategies for protection and the therapeutic management of AD.
- MeSH
- Alzheimerova nemoc patologie MeSH
- amyloidní plaky patologie MeSH
- hipokampus patologie MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- mikrocévy * metabolismus patologie MeSH
- modely nemocí na zvířatech MeSH
- potkani inbrední F344 MeSH
- potkani transgenní metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
Fischer 344 (F344) rats are characterized by the hyper-reactive hypothalamic-pituitary-adrenal axis to stressful stimuli, while Lewis (LEW) rats are considered to be hypo-reactive. We studied stress-induced cardiovascular, neuroendocrine, and behavioral responses of adult male F344 and LEW rats subjected to the single (120 min) or the repeated restraint stress (daily 120 min for 1 week). Mean arterial pressure (MAP) and heart rate (HR) were measured in the restrained rats (n = 7-8 for each group) via a catheter inserted into the femoral artery. Baroreceptor sensitivity was evaluated using NO donor sodium nitroprusside and α1-adrenoceptor agonist phenylephrine. The plasma levels of adrenocorticotropic hormone (ACTH), corticosterone, aldosterone, and adrenaline were determined before and during the restraint. Exploratory behavior was tested in open field test. F344 rats exerted the augmented stress-induced increase in plasma ACTH, corticosterone, and adrenaline as well as the impaired endocrine adaptation to the repeated stress compared to LEW rats. F344 rats exhibited higher MAP than LEW rats during single and repeated restraint. Moreover, repeatedly restrained F344 showed elevated HR and diminished baroreflex sensitivity. F344 and LEW rats exhibited similar total locomotor activity and the time spent in the center of open field arena, both parameters being decreased by the repeated restraint. The detailed analysis revealed altered pattern of locomotor behavior in F344 rats subjected to repeated restraint. In conclusion, F344 rats showed the impaired endocrine adaptation that resulted in allostatic overload, which might contribute to the impaired cardiovascular and behavioral adaptation to chronic stress observed in this strain. Lay summary F344 rats, characterized by HPA axis hyper-reactivity, exhibited higher blood pressure during restraint than LEW rats. Moreover, repeatedly restrained F344 rats showed elevated heart rate and impaired baroreflex sensitivity. It can be concluded that a poor adaptation to the repeated stress in F344 rats is not only limited to the neuroendocrine response but also has important cardiovascular consequences.
- MeSH
- fyzické omezení MeSH
- kortikosteron MeSH
- krysa rodu rattus MeSH
- potkani inbrední F344 MeSH
- potkani inbrední LEW MeSH
- psychický stres MeSH
- systém hypofýza - nadledviny * MeSH
- systém hypotalamus-hypofýza * MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
How the proliferation of the urothelium is regulated is known to a little degree. E. coli lipopolysaccharide (LPS) activates the innate immune response of the urinary bladder via the Toll-like receptor 4 (TLR4) on the urothelium but induces also urothelial proliferation. We wanted to assess whether muscarinic receptors are involved in the regulation of urothelial proliferation triggered by LPS stimulation. Female Fischer 344 rats were instilled with LPS or saline (control) in the urinary bladder in the absence or presence of muscarinic receptor blockade with atropine and regeneration of the urothelium was assessed 4h and 24h later. In the Fischer 344 bladder, urothelial thinning and urothelial caspase 3 up-regulation occurred at 4h after LPS urinary bladder instillation, which were totally blocked in rats pre-treated with atropine. TLR4 was only expressed in blood vessels in the Fischer 344 bladder, while it was also expressed in umbrella cells in the Sprague-Dawley bladder. Proliferation (Ki67 incorporation) of the human urothelial cell line UROtsa was reduced in the presence of the muscarinic receptor antagonists methoctramine (M2/M4-selective) and pirenzepine (M1/M4-selective), while proliferation instead was enhanced in the presence of atropine. In UROtsa cells exposed to LPS for 24h, 4-DAMP (M3/M1/M5-selective) inhibited instead proliferation. In conclusion, muscarinic receptors regulate urothelial proliferation and LPS may induce urothelial apoptosis via muscarinic receptor-dependent pathways. Our findings also suggest that species differences exist in the expressional pattern of TLR4 in the urothelium.
- MeSH
- apoptóza MeSH
- atropin farmakologie MeSH
- buněčné linie MeSH
- cholinergní látky farmakologie MeSH
- diaminy farmakologie MeSH
- Escherichia coli imunologie MeSH
- kaspasa 3 metabolismus MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- lipopolysacharidy imunologie MeSH
- pirenzepin farmakologie MeSH
- potkani inbrední F344 MeSH
- potkani Sprague-Dawley MeSH
- přirozená imunita MeSH
- proliferace buněk MeSH
- receptory muskarinové metabolismus MeSH
- toll-like receptor 4 metabolismus MeSH
- urotel patologie fyziologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The purpose of this study was to compare the effects of short-term fasting-induced rapid weight loss with those of slower but equivalent body weight loss induced by daily calorie restriction on muscle protein degradation pathways and muscle protein content. Male Fischer rats were subjected to either 30 % calorie restriction for 2 weeks to slowly decrease body weight (Slow) or 3-day fasting to rapidly decrease body weight by a comparable level of that of the Slow group (Rapid). The final body weights were about 15 % lower in both the Slow and Rapid groups than in the Con group (p<0.001). The total protein content and wet weight of fast-twitch plantaris muscle, but not slow-twitch soleus muscle, were significantly lower in the Rapid group compared with the control rats fed ad libitum. Substantial increases in the expression ratio of autophagosomal membrane proteins (LC3-II/-I ratio) and polyubiquitinated protein concentration, used as biomarkers of autophagy-lysosome and ubiquitin-proteasome activities, respectively, were observed in the plantaris muscle of the Rapid group. Moreover, the LC3-II/-I ratio and polyubiquitinated protein concentration were negatively correlated with the total protein content and wet weight of plantaris muscle. These results suggest that short-term fasting-induced rapid body weight loss activates autophagy-lysosome and ubiquitin-proteasome systems more strongly than calorie restriction-induced slower weight reduction, resulting in muscular atrophy in fast-twitch muscle.
- MeSH
- časové faktory MeSH
- hmotnostní úbytek fyziologie MeSH
- kalorická restrikce metody trendy MeSH
- kosterní svaly metabolismus MeSH
- krysa rodu rattus MeSH
- omezení příjmu potravy metabolismus MeSH
- potkani inbrední F344 MeSH
- proteolýza * MeSH
- signální transdukce fyziologie MeSH
- svalové proteiny metabolismus MeSH
- tělesná hmotnost fyziologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Methoxychlor (MXC) and vinclozolin (VIN) are well-recognized endocrine disrupting chemicals known to alter epigenetic regulations and transgenerational inheritance; however, non-endocrine disruption endpoints are also important. Thus, we determined the effects of MXC and VIN on the dysregulation of gap junctional intercellular communication (GJIC) and activation of mitogen-activated protein kinases (MAPKs) in WB-F344 rat liver epithelial cells. Both chemicals induced a rapid dysregulation of GJIC at non-cytotoxic doses, with 30 min EC50 values for GJIC inhibition being 10 µM for MXC and 126 µM for VIN. MXC inhibited GJIC for at least 24 h, while VIN effects were transient and GJIC recovered after 4 h. VIN induced rapid hyperphosphorylation and internalization of gap junction protein connexin43, and both chemicals also activated MAPK ERK1/2 and p38. Effects on GJIC were not prevented by MEK1/2 inhibitor, but by an inhibitor of phosphatidylcholine-specific phospholipase C (PC-PLC), resveratrol, and in the case of VIN, also, by a p38 inhibitor. Estrogen (ER) and androgen receptor (AR) modulators (estradiol, ICI 182,780, HPTE, testosterone, flutamide, VIN M2) did not attenuate MXC or VIN effects on GJIC. Our data also indicate that the effects were elicited by the parental compounds of MXC and VIN. Our study provides new evidence that MXC and VIN dysregulate GJIC via mechanisms involving rapid activation of PC-PLC occurring independently of ER- or AR-dependent genomic signaling. Such alterations of rapid intercellular and intracellular signaling events involved in regulations of gene expression, tissue development, function and homeostasis, could also contribute to transgenerational epigenetic effects of endocrine disruptors.
- MeSH
- androgenní receptory metabolismus MeSH
- buněčné linie MeSH
- insekticidy toxicita MeSH
- játra cytologie účinky léků metabolismus MeSH
- kmenové buňky účinky léků metabolismus MeSH
- konexin 43 metabolismus MeSH
- krysa rodu rattus MeSH
- MAP kinasový signální systém účinky léků MeSH
- methoxychlor toxicita MeSH
- mezerový spoj účinky léků MeSH
- mezibuněčná komunikace účinky léků MeSH
- mitogenem aktivované proteinkinasy p38 metabolismus MeSH
- oxazoly toxicita MeSH
- potkani inbrední F344 MeSH
- receptory pro estrogeny metabolismus MeSH
- signální transdukce účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
