Rat Model Of Alzheimer's Disease Research Articles

Using Deep Ocean Water in the Fermentation of Antrodia cinnamomea to Boost Magnesium Ion Bioabsorption and Anti-Inflammatory Effects in the Brain of an Alzheimer’s Disease Rat Model

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the deposition of amyloid β-peptide (Aβ) and subsequent oxidative inflammatory response, leading to brain damage and memory loss. This study explores the potential of Antrodia cinnamomea (AC), a Taiwan-native fungus known for its anti-inflammatory and antioxidant properties. The metabolites of AC, including dehydroeburicoic acid (DEA), 4-acetylantroquinonol B (4-AAQB), dehydrosulphurenic acid (DSA), and polysaccharides, were of particular interest. In the experiment, deep ocean water (DOW) was used to facilitate the solid-state fermentation of Antrodia cinnamomea NTTU 206 (D-AC), aiming to enhance its functional components. The impact of D-AC on the modulation of AD-related risk factors and the augmentation of cognitive abilities was subsequently evaluated in an AD rat model. This model was established via consecutive infusions of Aβ40 into the brain over a 28-day period. The administration of D-AC resulted in remarkable improvements in the rats’ reference memory, spatial probe test, and working memory. Notably, it restored the hippocampal magnesium levels by upregulating the expression of the magnesium transporter MAGT1. Concurrently, D-AC significantly downregulated the expressions of β-secretase 1 (BACE1) and the phosphorylated tau protein (p-tau), which were both implicated in AD progression. Additionally, it mitigated inflammatory responses, as suggested by the decreased levels of tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in the hippocampus and cerebral cortex. Ultimately, the ability of D-AC to restore the brain magnesium levels, attenuate inflammatory responses, and reduce hippocampal Aβ40 deposition led to significant improvements in the cognitive decline of AD rats. D-AC demonstrated a comparable efficacy with its counterpart, AC fruiting bodies (F-AC group), despite their componential differences. This study underscores the potential of D-AC, enriched through fermentation, as a novel dietary strategy for Alzheimer’s disease prevention.

Different ratios of Schisandra chinensis and Evodia rutaecarpa combination for treating Alzheimer's disease.

Schisandra chinensis and Evodia rutaecarpa are traditional Chinese herbs that have been used for many years to treat neurodegenerative diseases. In Chinese medicine, multiple herbs are often used in combination to enhance their efficacy, and different combination ratios can produce different therapeutic effects, thus flexibly responding to the needs of various patients. This study aimed to investigate the effects of different ratios of Schisandra and Evodia herbs on learning and memory impairment in rats with Alzheimer's disease (AD) and their specific mechanisms of action. Morris water maze and hematoxylin and eosin (HE) staining experiments were performed to evaluate the effects of different ratios of Schisandra-Evodia on learning memory in AD model rats. Immunohistochemical experiments were performed to investigate the effects of Schisandra-Evodia on the Aβ1-42 and P-Tau proteins, and protein immunoblotting (WB) was performed to determine the expression of key proteins in two pathways, BDNF/TrkB/CREB and GSK-3β/Tau. Our experimental results show that all Schisandra-Evodia groups showed significant neuroprotective effects, improved learning memory impairment, and reduced levels of Aβ1-42 and P-Tau proteins in AD model rats. Schisandra-Evodia upregulated BDNF, P-TrkB/TrkB, and P-CREB/CREB protein expression and downregulated GSK-3β and P-Tau/Tau protein expression. Among the different Schisandra-Evodia ratio groups, the 2:1 group showed the strongest therapeutic effect on AD. Our research results indicate that Schisandra-Evodia can reduce Aβ1-42 and P-Tau protein content by modulating the activity of two pathways, BDNF/TrkB/CREB and GSK-3β/Tau, thus improving neuronal cell damage and cognitive deficits caused by AD. In addition, we found that a Schisandra-Evodia ratio of 2:1 had the most profound therapeutic effect on AD.

The Effect of Aerobic Training and Resveratrol on Ferroptosis in a Rat Model of Alzheimer's Disease

The Effect of Aerobic Training and Resveratrol on Ferroptosis in a Rat Model of Alzheimer's Disease

Memory impairment was ameliorated by corticolimbic microinjections of arachidonylcyclopropylamide (ACPA) and miRNA-regulated lentiviral particles in a streptozotocin-induced Alzheimer's rat model

The present study aimed to investigate the effect of corticolimbic cannabinoid CB1 receptors activity on memory impairment in the intracerebroventricular (ICV)-streptozotocin (STZ) animal model of Alzheimer's like-disease. This study also assessed whether the corticolimbic overexpression of miRNA-137 or -let-7a could increase the endocannabinoids by inhibiting the monoglyceride lipase (MAGL) to ameliorate STZ response. The results showed that ICV microinjection of STZ (3 mg/kg/10 μl) impaired passive avoidance memory retrieval. The chronic microinjection of arachidonylcyclopropylamide (ACPA; 10 ng/0.5 μl), a selective cannabinoid CB1 receptor agonist, into the hippocampal CA1 region, the central amygdala (CeA) or the medial prefrontal cortex (mPFC) ameliorated the amnesic effect of ICV-STZ. Intra-CA1 or -CeA microinjection of ACPA alone did not affect memory retrieval, while its microinjection into the mPFC impaired memory formation. Based on bioinformatics analysis and verification of the MAGL gene, miRNA-137 and -let-7a were chosen to target the expression levels of MAGL in the corticolimbic regions. The chronic corticolimbic microinjection of lentiviral particles containing miRNA-137 or -let-7a ameliorated ICV-STZ-induced memory impairment. The high transfection efficiency was determined for each virus using comparing fluorescent and conventional vision. Corticolimbic overexpression of miRNA-137 or -let-7a decreased the MAGL gene expression that encodes the MAGL enzyme to increase the endocannabinoids. Thus, among the molecular mechanisms and signaling pathways involved in the pathophysiology of Alzheimer's disease (AD), it is worth mentioning the role of endocannabinoids in the corticolimbic regions. CB1 receptor agonists, miRNA-137 or -let-7a, may be potential therapeutic targets against cognitive decline in AD.

Phosphorylation of MAP 1A regulates hyperphosphorylation of Tau in Alzheimer's disease model.

Hyperphosphorylation of Tau is one of the important pathological features of Alzheimer's disease (AD). Therefore, studying the mechanisms behind Tau hyperphosphorylation is crucial in exploring the pathogenesis of neurological damage in AD. In this study, after the establishment of rat models of AD, quantitative phosphoproteomics and proteomics were performed to identify proteins, showing that phosphorylation of microtubule associated protein 1A (MAP 1A) was lower in the model group. Western blot confirmed the changes of MAP 1A in the SD rats, APP/PS1 transgenic mice and cell AD models. To further study the molecular mechanism of recombinant MAP 1A phosphorylation affecting Tau phosphorylation, interfering siRNA-MAP 1A and protein immunoprecipitation reaction analysis were performed in AD cell models. Cyclin-dependent kinase 5 (CDK5) showed reduced binding to MAP 1A and increased binding to Tau, resulting in a decrease in phosphorylated MAP 1A (p-MAP 1A) and an increase in phosphorylated Tau (p-Tau), and MAP 1A silencing promoted binding of CDK5-Tau and increased Tau phosphorylation, thereby reducing the cell survival rate. In summary, we found that p-MAP 1A downregulation associated with p-Tau upregulation was due to their altered binding forces to CDK5, and MAP 1A could enhance autophosphorylation by competitive binding to CDK5 and antagonise Tau phosphorylation. This leads to neuronal protection and reducing tissue damage levels in AD, which can help better understand the mechanisms of AD pathogenesis.

Chrysophanol improves memory impairment and cell injury by reducing the level of ferroptosis in Aβ25-35 treated rat and PC12 cells.

Alzheimer's disease (AD) is a common age-related chronic and neurodegenerative disease that has become a global health problem. AD pathogenesis is complex, and the clinical efficacy of commonly used anti-AD drugs is suboptimal. Recent research has revealed a close association between AD-induced damage and the activation of ferroptosis signaling pathways. Chrysophanol (CHR) the principal medicinal component of Rhubarb, has been reported to have anti-AD effects and can reduce ROS levels in AD-damaged models. AD has been linked to the activation of ferroptosis signaling pathways, which has an important feature of higher levels of reactive oxygen species (ROS). Therefore, the present study explored whether CHR had an anti-AD effect by regulating the ferroptosis levels in AD injury models. Morris water maze, novel object recognition test, Y-maze test, Hematoxylin-eosin (H&E) staining, western blotting, ROS measurement, GPx activity measurement, LPO measurement, transmission electron microscopy, live/dead cell staining were used to investigate the changes in spatial memory level and ferroptosis level in AD model, and the intervention effect of CHR. CHR improved the spatial memory level of AD rat models, reduced the level of hippocampal neuron damage, and improved the survival rate of PC12 cells damaged by β-amyloid (Aβ). Meanwhile, CHR increased glutathione peroxidase-4 (GPX4) protein expression, GPx activity, and GSH, decreased ROS and LPO levels in AD rat models and Aβ-damaged PC12 cells, and improved mitochondrial pathological damage. Our findings suggest that CHR may play a protective role in AD injury by lowering ferroptosis levels, which may provide a potential pathway for developing drugs for AD. However, the mechanism of CHR's role requires further investigation.

TgF344-AD Rat Model of Alzheimer's Disease: Spatial Disorientation and Asymmetry in Hemispheric Neurodegeneration.

The TgF344-AD ratline represents a transgenic animal model of Alzheimer's disease. We previously reported spatial memory impairment in TgF344-AD rats, yet the underlying mechanism remained unknown. We, therefore, set out to determine if spatial memory impairment in TgF344-AD rats is attributed to spatial disorientation. Also, we aimed to investigate whether TgF344-AD rats exhibit signs of asymmetry in hemispheric neurodegeneration, similar to what is reported in spatially disoriented AD patients. Finally, we sought to examine how spatial disorientation correlates with working memory performance. TgF344-AD rats were divided into two groups balanced by sex and genotype. The first group underwent the delayed match-to-sample (DMS) task for the assessment of spatial orientation and working memory, while the second group underwent positron emission tomography (PET) for the assessment of glucose metabolism and microglial activity as in-vivo markers of neurodegeneration. Rats were 13 months old during DMS training and 14-16 months old during DMS testing and PET. In the DMS task, TgF344-AD rats were more likely than their wild-type littermates to display strong preference for one of the two levers, preventing working memory testing. Rats without lever-preference showed similar working memory, regardless of their genotype. PET revealed hemispherically asymmetric clusters of increased microglial activity and altered glucose metabolism in TgF344-AD rats. TgF344-AD rats display spatial disorientation and hemispherically asymmetrical neurodegeneration, suggesting a potential causal relationship consistent with past clinical research. In rats with preserved spatial orientation, working memory remains intact.

Therapeutic potential of bitter taste receptor agonists on amyloid β-induced rat model of Alzheimer’s disease

ABSTRACT This study was conducted to investigate the effect of bitter taste receptor (T2R) agonists (caffeine and extracts of myrrh and Boswellia serrata) on amyloid β (Aβ)-induced Alzheimer’s disease (AD) in rats. Rats intracerebroventricularly (ICV) injected with a single dose of Aβ (3 μg/μL/rat) had significantly: 1) lower brain weight, 2) higher short-term memory impairment, 3) lower serum dopamine level, 4) higher AChE activity, 5) higher brain lipid peroxide malonaldehyde, 6) lower brain antioxidant activities of catalase, superoxide dismutase and glutathione peroxidase, 7) higher brain phosphor tau protein level, 8) higher brain levels of apoptotic markers (Bax and caspase 3), 9) lower brain level of antiapoptotic marker Bcl2, 10) downregulated brain expression of the bitter receptor (T2R4) gene, 11) upregulated brain expression of tumor necrosis factor α (TNFα) and nuclear factor κB (NF-κB) genes and 12) marked neuronal degeneration associated with severe vacuolation of neutrophils. All deteriorated effects of Aβ were restored following treatment with caffeine (20 mg/kg), myrrh aqueous extract (10 mg/kg) and Boswellia serrata aqueous extract (400 mg/kg) with best effect for myrrh aqueous extract. These data conclude that bitter taste receptor agonists (caffeine and extracts of myrrh and Boswellia serrata) had therapeutic potential on amyloid β-induced rat model of Alzheimer’s disease.

Protective effect of a standardized Allium jesdianum extract in an Alzheimer's disease induced rat model

Alzheimer's disease (AD) is a complex disorder with multiple underlying mechanisms. Existing treatment options mostly address symptom management and are associated with numerous side effects. Therefore, exploring alternative therapeutic agents derived from medicinal plants, which contain various bioactive compounds with diverse pharmacological effects, holds promise for AD treatment. This study aims to assess the protective effects of the hydroalcoholic extract of Allium jesdianum on cognitive dysfunction, mitochondrial and cellular parameters, as well as genetic parameters in an intracerebroventricular Streptozotocin (icv-STZ) induced rat model of AD. Male Wistar rats were injected with a single dose of STZ (3 mg/kg, icv) to establish a sporadic AD model. A. jesdianum extract (100, 200, and 400 mg/kg/day) and donepezil (5 mg/kg/day) were orally administered for 14 days following model induction. Cognitive function was evaluated using the radial arm water maze test. Mitochondrial toxicity parameters in various brain regions (whole brain, frontal cortex, hippocampus, and cerebellum) were assessed. Gene expression analysis of miR-330, miR-132, Bax, and Bcl-2 in isolated rat brain neurons was performed using RT-qPCR. A. jesdianum extract significantly attenuated cognitive dysfunction and mitigated mitochondrial toxicity induced by icv-STZ administration. Following STZ injection, there was upregulation of Bax gene expression and downregulation of miR-330, miR-132, and Bcl-2 gene expression. Treatment with A. jesdianum extract resulted in the reversal of the expression of these microRNAs and genes, indicating its potential for improving AD and reducing neuronal apoptosis. This study demonstrates the neuroprotective capabilities of A. jesdianum against STZ-induced oxidative stress and cognitive impairment in rats, highlighting its therapeutic potential in the management of AD.

The effects of carvacrol and p-cymene on Aβ1-42 -induced long-term potentiation deficit in male rats.

Alzheimer's disease (AD) is the most common type of dementia in which oxidative stress plays an important role. In this disease, learning and memory and the cellular mechanism associated with it, long-term potentiation (LTP), are impaired. Considering the beneficial effects of carvacrol (CAR) and p-cymene against AD, their effect was assessed on in vivo hippocampal LTP in the perforant pathway (PP)-dentate gyrus (DG) pathway in an Aβ1-42 -induced rat model of AD. Male Wistar rats were randomly assigned to five groups: sham: intracerebroventricular (ICV) injection of phosphate-buffered saline, Aβ: ICV Aβ1-42 injections, Aβ + CAR (50 mg/kg), Aβ + p-cymene (50 mg/kg), and Aβ + CAR + p-cymene. Administration of CAR and p-cymene was done by gavage daily 4 weeks before and 4 weeks after the Aβ injection. The population spike (PS) amplitude and field excitatory postsynaptic potentials (fEPSP) slope were determined in DG against the applied stimulation to the PP. Aβ-treated rats exhibited impaired LTP induction in the PP-DG synapses, resulting in significant reduction in both fEPSP slope and PS amplitude compared to the sham animals. Aβ-treated rats consumed either CAR or p-cymene separately (but not their combination), and showed an enhancement in fEPSP slope and PS amplitude of the DG granular cells. These data indicate that CAR or p-cymene can ameliorate Aβ-associated changes in synaptic plasticity. Surprisingly, the combination of CAR and p-cymene did not yield the same effect, suggesting a potential interaction between the two substances.

Valine conjugated polymeric nanocarriers for targeted co-delivery of rivastigmine and quercetin in rat model of Alzheimer disease

Multifunctional nanocarriers are increasingly promising for disease treatment aimed at finding effective therapy and overcoming barriers in drug delivery. Herein, valine conjugated chitosan (VLCS) was used for surface modification of nanocarriers (NCs) based on Poly (ε-caprolactone)-Poly (ethylene glycol)-Poly (ε-caprolactone) (PCL-PEG-PCL) triblock copolymers (NCs@VLCS). The nanocarriers were co-loaded with rivastigmine (RV) and quercetin (QT) to yield the final RV/QT-NCs@VLCS as a multifunctional nanocarrier for Alzheimer’s disease (AD) treatment. The large amino acid transporter 1 (LAT-1) was selected for the direction of the NCs to the brain. The biocompatibility of the nanocarrier was studied in HEK-293 and SH-SY5Y cells and rats. The Morris water maze test demonstrated a faster regain of memory loss with RV/QT-NCs@VLCS compared to the other groups. Furthermore, RV/QT-NCs@VLCS and RV/QT-NCs improved GSH depletion induced by scopolamine (SCO), with RV/QT-NCs@VLCS having a superior effect. The real-time PCR analysis revealed that co-delivery of RV and QT by NCs@VLCS showed significantly higher efficacy than sole delivery of RV. RV/QT-NCs@VLCS treatment also modulated the expression of BDNF, ACHE, and TNF-α. The findings revealed that NCs@VLCS co-loaded with RV and QT, significantly increased efficacy relative to the single use of RV and could be considered a potent multifunctional drug delivery system for Alzheimer’s treatment.

Comparison of the efficacy of human umbilical cord mesenchymal stem cells conditioned medium and platelet-rich plasma on the hippocampus of STZ–induced rat model of Alzheimer’s disease: A behavioral and stereological study

IntroductionAlzheimer’s disease (AD) is accompanied by progressive cognitive disorders and memory loss. This study aims to determine the combined effects of conditioned medium of human umbilical cord mesenchymal stem cells (CM) and platelet-rich plasma (PRP) on AD model rats. MethodsForty-eight male Sprague Dawley rats were classified into 6 groups: Control, Sham, AD, and three treatment groups. AD was induced by streptozotocin(STZ; 3 mg/kg, intracerebroventricular (ICV)) and the treatment groups received injections of CM [(200 µl, intraperitoneally (i.p.), and/or PRP (100 µl, intravenously(i.v)] for 8 days. Behavioral tests (Morris water maze and novel objective recognition) were used to assess learning ability and memory. At the end of the behavioral tests, the rats were sacrificed and their brain was entirely removed, sectioned, and stained with cresyl violet. The hippocampus volume and number of neurons were evaluated by stereological techniques. ResultsIn the AD group, the discrimination ratio, time spent in the target zone, volume of Cornu Ammonis1 (CA1) and Dentate Gyrus (DG), and the number of pyramidal and granular cells decreased significantly compared to the Sham group. The mentioned parameters increased in the CM and CM+PRP groups compared to the AD group (p < 0.01). PRP did not have any noticeable effect on the examined parameters. ConclusionsCM may be beneficial in the treatment of AD as it led to better improvement in STZ-induced learning and memory impairments as well as the structure of the hippocampus.

Intracellular Amyloid-β in the Normal Rat Brain and Human Subjects and Its relevance for Alzheimer's Disease.

Amyloid-β (Aβ) is a normal product of neuronal activity, including that of the aggregation-prone Aβ42 variant that is thought to cause Alzheimer's disease (AD). Much knowledge about AD comes from studies of transgenic rodents expressing mutated human amyloid-β protein precursor (AβPP) to increase Aβ production or the Aβ42/40 ratio. Yet, little is known about the normal expression of Aβ42 in rodent brains. To characterize the brain-wide expression of Aβ42 throughout the life span of outbred Wistar rats, and to relate these findings to brains of human subjects without neurological disease. Aβ42 immunolabeling of 12 Wistar rat brains (3-18 months of age) and brain sections from six human subjects aged 20-88 years. In healthy Wistar rats, we find intracellular Aβ42 (iAβ42) in neurons throughout the brain at all ages, but levels vary greatly between brain regions. The highest levels are in neurons of entorhinal cortex layer II, alongside hippocampal neurons at the CA1/subiculum border. Concerning entorhinal cortex layer II, we find similarly high levels of iAβ42 in the human subjects. Expression of iAβ42 in healthy Wistar rats predominates in the same structures where iAβ accumulates and Aβ plaques initially form in the much used, Wistar based McGill-R-Thy1-APP rat model for AD. The difference between wild-type Wistar rats and these AD model rats, with respect to Aβ42, is therefore quantitative rather that qualitative. This, taken together with our human results, indicate that the McGill rat model in fact models the underlying wild-type neuronal population-specific vulnerability to Aβ42 accumulation.

RETRACTED: Gelatin/polyethylene glycol-loaded magnesium hydroxide nanocomposite to attenuate acetylcholinesterase, neurotoxicity, and activation of GPR55 protein in rat models of Alzheimer's disease

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/locate/withdrawalpolicy).This article has been retracted at the request of the Editor-in-Chief.Following concerns raised by an anonymous reader regarding Figs. 7 and 8, specifically that images from different dose groups appear to overlap, the journal conducted a thorough investigation. The corresponding author, Dr. Soundarapandian Kannan, submitted corrected figures and requested a corrigendum. After careful examination and consultation with the board, the Editor-in-Chief determined that the revised figures did not satisfactorily address the concerns presented and a retraction is warranted.The scientific community takes a very strong view on this matter and apologies are offered to readers of the journal that this was not detected during the submission process.

An interventional study of baicalin on neuronal pentraxin-1, neuronal pentraxin-2, and C-reactive protein in Alzheimer's disease rat model.

Baicalin has been shown to promote spatial learning and neural regeneration, which might increase the differentiation of neural stem cells in Alzheimer's disease (AD) rat models. We aimed to study the role of baicalin on neuronal pentraxin-1 (NPTX-1), neuronal pentraxin-2 (NPTX-2), and C-reactive protein (CRP) in AD model rats. The 30 male Sprague Dawley rats were divided into three groups: the control group, the AD model group, and the AD + baicalin group. Then, the Morris water maze was used to verify the effect of baicalin on the memory and spatial learning of rats. Immunohistochemistry and immunofluorescence were used to observe the expression of NPTX-1, NPTX-2, and CRP in brain tissue. Compared with the AD model group, the AD rats treated with baicalin spent significantly less time finding escape latencies (P = 0.008) and had longer cross-platform times in the target quadrant (P = 0.015). In addition, the AD + baicalin group had significantly higher numbers of hippocampal neurons compared with the AD model group (P < 0.05). Baicalin also obviously decreased the apoptosis of neurons. Moreover, compared with the AD model group, the NPTX-1 and CRP expression in the AD + baicalin group was significantly reduced (P = 0.000) while the expression of NPTX-2 in the brain tissue of AD rats was significantly increased (P = 0.000). Baicalin can play a therapeutic role by downregulating NPTX-1, upregulating NPTX-2, and downregulating CPR in AD model rats.

Voglibose attenuates cognitive impairment, Aβ aggregation, oxidative stress, and neuroinflammation in streptozotocin-induced Alzheimer's disease rat model.

Alzheimer's disease (AD) is an age-dependent neurodegenerative disease hallmarked by Amyloid-β (Aβ) aggregation, cognitive impairment, and neuronal and synaptic loss. In this study, AD was induced in male Wistar rats (n = 6) by the administration of intracerebroventricular-streptozotocin (ICV-STZ-3mg/kg/day), and Voglibose (Vog) was administered at various doses (10, 25, and 50mg/kg), while Galantamine (3mg/kg) acted as a reference standard drug. Behavioral alterations in both spatial and non-spatial memory functions were evaluated in the experimental rats. At the end of the study, all experimental rats were sacrificed, and their brain parts, the cortex and hippocampus, were subjected to biochemical, western blot, and histopathological analysis. In our study results, the statistically significant dose-dependent results from the behavioral tests show the Voglibose-treated groups significantly improved (p < 0.0001) spatial and non-spatial memory functions when compared with ICV-STZ-treated group. Meanwhile, when compared with ICV-STZ-treated rats, treatment with Voglibose (10, 25, and 50mg/kg) showed the activities of both acetylcholinesterase (AChE) and malondialdehyde (MDA) were significantly attenuated (p < 0.0001), while the operation of antioxidant enzymes was considerably enhanced (p < 0.0001). The molecular estimation showed that it significantly attenuates (p < 0.0001) the TNF-α, IL-1β, and CRP activity, and the western blot results demonstrate the significantly attenuated Aβ aggregation. The histopathological results showed that the Voglibose treatment had an effective improvement in clear cytoplasm and healthy neuronal cells. In conclusion, our results suggest that Voglibose has potent neuroprotective effects against the ICV-STZ-induced AD model. Furthermore, these results support the possibility of Voglibose as a therapeutic approach to improving cognitive function, suggesting that controlling Aβ aggregation might be a novel target for the development of AD.

Astrocytic AT1R deficiency ameliorates Aβ-induced cognitive deficits and synaptotoxicity through β-arrestin2 signaling.

Alzheimer's disease (AD) seriously influences human health, and there is no effective treatment to prevent or cure AD. Recent studies have shown that angiotensin II type 1 receptor (AT1R) blockers significantly reduce the prevalence of AD, while the precise role and mechanism of AT1R in AD remain obscure. In this study, for the first time, we identified that astrocytic but not neuronal AT1R levels were significantly increased in AD model rats and found that astrocyte-specific knockout of AT1R significantly ameliorated amyloid β (Aβ)-induced cognitive deficits and synaptotoxicity. Pretreating astrocytes with an AT1R blocker also alleviated Aβ-induced synaptotoxicity in the coculture system of hippocampal neurons and astrocytes. Moreover, AT1R could directly bind to Aβ1-42 and activate the astrocytic β-arrestin2 pathway in a biased manner, and biased inhibition of the astrocytic AT1R/β-arrestin2 pathway relieved Aβ-induced neurotoxicity. Furthermore, we demonstrated that astrocytic AT1R/β-arrestin2 pathway-mediated synaptotoxicity was associated with the aggregation of autophagosomes, which triggered the disordered degradation of Aβ. Our findings reveal a novel molecular mechanism of astrocytic AT1R in Aβ-induced neurodegeneration and might contribute to establishing new targets for AD prevention and therapy.

Gamma-patterned sensory stimulation reverses synaptic plasticity deficits in rat models of early Alzheimer's disease.

Non-invasive sensory stimulation in the range of the brain's gamma rhythm (30-100 Hz) is emerging as a new potential therapeutic strategy for the treatment of Alzheimer's disease (AD). Here, we investigated the effect of repeated combined exposure to 40 Hz synchronized sound and light stimuli on hippocampal long-term potentiation (LTP) in vivo in three rat models of early AD. We employed a very complete model of AD amyloidosis, amyloid precursor protein (APP)-overexpressing transgenic McGill-R-Thy1-APP rats at an early pre-plaque stage, systemic treatment of transgenic APP rats with corticosterone modelling certain environmental AD risk factors and, importantly, intracerebral injection of highly disease-relevant AD patient-derived synaptotoxic beta-amyloid and tau in wild-type animals. We found that daily treatment with 40 Hz sensory stimulation for 2 weeks fully abrogated the inhibition of LTP in all three models. Moreover, there was a negative correlation between the magnitude of LTP and the level of active caspase-1 in the hippocampus of transgenic APP animals, which suggests that the beneficial effect of 40 Hz stimulation was dependent on modulation of pro-inflammatory mechanisms. Our findings support ongoing clinical trials of gamma-patterned sensory stimulation in early AD.

Synapsin 1 Ameliorates Cognitive Impairment and Neuroinflammation in Rats with Alzheimer's Disease: An Experimental and Bioinformatics Study.

Alzheimer's disease (AD) is a persistent neuropathological injury that manifests via neuronal/synaptic death, age spot development, tau hyperphosphorylation, neuroinflammation, and apoptosis. Synapsin 1 (SYN1), a neuronal phosphoprotein, is believed to be responsible for the pathology of AD. This study aimed to elucidate the exact role of SYN1 in ameliorating AD and its potential regulatory mechanisms. The AD dataset GSE48350 was downloaded from the GEO database, and SYN1 was focused on differential expression analysis and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. After establishing an AD rat model, they were treated with RNAi lentivirus to trigger SYN1 overexpression. The amelioration of SYN1 in AD-associated behavior was validated using multiple experiments (water maze test and object recognition test). SYN1's repairing effect on the important factors in AD was confirmed by detecting the concentration of inflammatory factors (interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α), neurotransmitters (acetylcholine (ACh), dopamine (DA), and 5-hydroxytryptophan (5-HT)) and markers of oxidative stress (glutathione (GSH), malondialdehyde (MDA), reactive oxygen species (ROS)). Molecular biology experiments (qRT-PCR and western blot) were performed to examine AD-related signaling pathways after SYN1 overexpression. Differential expression analysis yielded a total of 545 differentially expressed genes, of which four were upregulated and 541 were downregulated. The enriched pathways were basically focused on synaptic functions, and the analysis of the protein- protein interaction network focused on the key genes in SYN1. SYN1 significantly improved the spatial learning and memory abilities of AD rats. This enhancement was reflected in the reduced escape latency of the rats in the water maze, the significantly extended dwell time in the third quadrant, and the increased number of crossings. Furthermore, the results of the object recognition test revealed reduced time for rats to explore familiar and new objects. After SYN1 overexpression, the cAMP signaling pathway was activated, the phosphorylation levels of the CREB and PKA proteins were elevated, and the secretion of neurotransmitters such as ACh, DA, and 5-HT was promoted. Furthermore, oxidative stress was suppressed, as supported by decreased levels of MDA and ROS. Regarding inflammatory factors, the levels of IL-6, IL-1β, and TNF-α were significantly reduced in AD rats with SYN1 overexpression. SYN1 overexpression improves cognitive function and promotes the release of various neurotransmitters in AD rats by inhibiting oxidative stress and inflammatory responses through cAMP signaling pathway activation. These findings may provide a theoretical basis for the targeted diagnosis and treatment of AD.

Effect of exercise on the hypothalamic–pituitary–gonadal axis in a rat model of Alzheimer’s disease

Hypothalamic–pituitary–gonadal (HPG) axis dysregulation was suggested to play a crucial role in Alzheimer’s disease (AD). This study investigated the effects of exercise on HPG hormones in an AD rat model, as a possible mechanism underlying the favorable effect of exercise on AD. Forty male Wistar albino rats 2–3 months old were subdivided randomly into two groups (n = 20 each): AD group (injected intraperitoneally with aluminum chloride (70 mg/kg/day) for 6 weeks) and Control group. Each group was subdivided into exercised or non-exercised group (n = 10 each). Exercised groups were subjected to a swimming protocol (60 min/day, 5 days/week, 4 weeks). Serum HPG hormones, hippocampal β-amyloid levels and Morris water-maze cognition were assessed. Results demonstrated higher levels of β-amyloid, gonadotropin releasing hormone (GnRH), luteinizing hormone (LH) and follicle stimulating hormone (FSH) together with lower testosterone levels and cognitive impairment in the AD rats compared to controls. Β-amyloid levels negatively correlated with testosterone levels and positively correlated with GnRH, LH and FSH among the AD rats. Higher testosterone and lower GnRH, LH, FSH and β-amyloid levels, as well as cognitive improvement, were observed in the exercised compared to non-exercised AD rats, suggesting a modulatory role of exercise training on AD-associated HPG axis dysregulation.