Rat Model Of Alzheimer's Disease Research Articles

Effects of diverse Types of Toxoplasma gondii on the outcome of Alzheimer's disease in the rat model.

Toxoplasma gondii has lifelong persistence in the brain and its cysts can affect gene expression and change diverse biological functions of neurons. Many studies indicated T. gondii infection as a risk factor for the development of behavioral changes and neurodegenerative diseases such as Alzheimer's disease (AD), although the etiopathogenetic link between them has not been exactly elucidated. The current study aimed to examine the effects of chronic toxoplasmosis infection with Types I, II, and III strains (RH, PRU, and VEG) alone and in combination on cognitive impairments and neuronal death in the Aβ1-42-induced rat model of Alzheimer's disease. In the chronic toxoplasmosis phase, Alzheimer's induction was conducted by injecting Aβ1-42 oligomers into the rat brain hippocampus. Behavioral tests were conducted 10 days after the AD induction. Real-time PCR was performed to evaluate T. gondii parasite burden by amplification of the B1 gene. Cytokines IL-1β, TNF-α, and IL-10 were assayed in brain tissue supernatant using ELISA. Also, histopathological examinations were conducted to calculate inflammatory changes and neuronal death in the brain. Our findings showed that chronic toxoplasmosis infection with PRU reduces cognitive disorders, while the RH strain of T. gondii plays a destructive role and aggravates cognitive impairments in AD. Also, infection with a combination of PRU and VEG strains significantly improved spatial learning and memory impairments in Alzheimer's rat model. Histopathological findings also confirmed the results of behavioral tests, so that in AβPRU and AβPRU+VEG groups, neuronal death and infiltration of inflammatory cells were negligible and significantly less than in Alzheimer's and AβRH groups. Our findings indicate that chronic toxoplasmosis infection with PRU strain alone, also in combination with VEG strain can significantly improve cognitive disorders in AD rats, while RH strain plays a destructive role in AD pathogenesis.

Sleep deprivation aggravated amyloid β oligomers-induced damage to the cerebellum of rats: Evidence from magnetic resonance imaging

For quite a long time, researches on Alzheimer's disease (AD) primarily focused on the cortex and hippocampus, while the cerebellum has been ignored because of its abnormalities considered to appear in the late stage of AD. In recent years, increasing evidence suggest that the cerebellar pathological changes possibly occur in the preclinical phase of AD, which is also associated with sleep disorder. Sleep disturbance is a high risk factor of AD. However, the changes and roles of cerebellum has rarely been reported under conditions of AD accompanied with sleep disorders. In this study, using an amyloid-β oligomers (AβO)-induced rat model of AD subjected to sleep deprivation, combining with a 7.0 T animals structural magnetic resonance imaging (MRI), we assessed structural changes of cerebellum in MRI. Our results showed that sleep deprivation combined with AβO led to an increased FA value in the anterior lobe of cerebellum, decreased ADC value in the cerebellar lobes and cerebellar nuclei, and increased cerebellum volume. Besides that, sleep deprivation exacerbated the damage of AβO to the cerebellar structural network. This study demonstrated that sleep deprivation could aggravate the damage to cerebellum induced by AβO. The present findings provide supporting evidence for the involvement of cerebellum in the early pathology of AD and sleep loss. Our data would contribute to advancing the understanding of the mysterious role of cerebellum in AD and sleep disorders, as well as would be helpful for developing non-invasive MRI biomarkers for screening early AD patients with self-reported sleep disturbances.

High-intensity interval training ameliorates Alzheimer's disease-like pathology by regulating astrocyte phenotype-associated AQP4 polarization.

Background: Alzheimer's disease (AD), one of the most common forms of dementia, is a widely studied neurodegenerative disease characterized by Aβ accumulation and tau hyperphosphorylation. Currently, there is no effective cure available for AD. The astrocyte AQP4 polarized distribution-mediated glymphatic system is essential for Aβ and abnormal tau clearance and is a potential therapeutic target for AD. However, the role of exercise on the AQP4 polarized distribution and the association between the AQP4 polarized distribution and astrocyte phenotype polarization are poorly understood. Methods: Using a streptozotocin (STZ)-induced sporadic AD rat model, we investigated the effects of high-intensity interval training on AD pathologies. The Branes maze task was conducted to measure spatial learning and memory. Immunofluorescence staining of NeuN with TUNEL, Fluoro-Jade C, and relative neuronal damage markers was applied to measure neuronal apoptosis, neurodegeneration, and damage. Sholl analysis was carried out to analyze the morphology of microglia. Line-scan analysis, 3D rendering, and the orthogonal view were applied to analyze the colocalization. Western blot analysis and enzyme-linked immunosorbent assay (ELISA) analysis were conducted to examine AQP4 and Aβ, respectively. An APP/PS1 transgenic AD mice model was used to confirm the key findings. Results: High-intensity interval training (HIIT) alleviates cognitive dysfunction in STZ-induced AD-like rat models and provides neuroprotection against neurodegeneration, neuronal damage, and neuronal loss. Additionally, HIIT improved the drainage of abnormal tau and Aβ from the cortex and hippocampus via the glymphatic system to the kidney. Further mechanistic studies support that the beneficial effects of HIIT on AD might be due, in part, to the polarization of glial cells from a neurotoxic phenotype towards a neuroprotective phenotype. Furthermore, an intriguing finding of our study is that the polarized distribution of AQP4 was strongly correlated with astrocyte phenotype. We found A2 phenotype exhibited more evident AQP4 polarization than the A1 phenotype. Conclusion: Our findings indicate that HIIT ameliorates Alzheimer's disease-like pathology by regulating astrocyte phenotype and astrocyte phenotype-associated AQP4 polarization. These changes promote Aβ and p-tau clearance from the brain tissue through the glymphatic system and the kidney.

Sideritis species-loaded poly(lactic acid-co-glycolic acid) nanoparticles improved memory and learning in an Intracerebroventricular amyloid-β1–42 rat model of Alzheimer’s disease

Sideritis species-loaded poly(lactic acid-co-glycolic acid) nanoparticles improved memory and learning in an Intracerebroventricular amyloid-β1–42 rat model of Alzheimer’s disease

The TgF344-AD rat: behavioral and proteomic changes associated with aging and protein expression in a transgenic rat model of Alzheimer's disease

Animal models of Alzheimer's Disease (AD) are attractive tools for preclinical, prodromal drug testing. The TgF344-AD (Tg) rat exhibits cognitive deficits and 5 major hallmarks of AD. Here we show that spatial water maze (WMZ) memory deficits and proteomic differences in dorsal CA1 were present in young Tg rats. Aged learning-unimpaired (AU) and aged learning-impaired (AI) proteome associated changes were identified and differed by sex. Levels of phosphorylated tau, reactive astrocytes and microglia were significantly increased in aged Tg rats and correlated with the WMZ learning index (LI); in contrast, no significant correlation was present between amyloid plaques or insoluble Aβ levels and LI. Neuroinflammatory markers were also significantly correlated with LI and increased in female Tg rats. The anti-inflammatory marker, triggering receptor expressed on myeloid cells-2 (TREM2), was significantly reduced in aged impaired Tg rats and correlated with LI. Identifying and understanding mechanisms that allow for healthy aging by overcoming genetic drivers for AD, and/or promoting drivers for successful aging, are important for developing successful therapeutics against AD.

Study on multi-target effects of PIMPC on Aβ/Cu2+-induced Alzheimer's disease model of rats

Glycogen synthase kinase-3 (GSK-3), a key role in the pathogenesis of Alzheimer's disease (AD), has been linked with the formation of β-amyloid (Aβ), tubulin-associated unit (tau) protein phosphorylation and apoptosis. Moreover, the excessive presence of elements such as copper (Cu) can promote Aβ aggregation and increase the risk of AD. Combined with the role of GSK-3 and metal elements in AD, a metal-chelating imine GSK-3 inhibitor N-(4-{[(2-amino-5-phenylpyridin-3-ylidene)imino]methyl}pyridin-2-yl)cyclopropanecarboxamide (PIMPC) was designed and synthesized. In our study, Aβ/Cu2+-induced AD rat model was established and treated with PIMPC. The results indicated that PIMPC can not only down-regulate the high expression levels of Aβ, tau and p-tau proteins of the AD rats, but also chelate Cu and aluminum (Al) elements in the brain. In addition, PIMPC may play an anti-apoptotic effect by down-regulating the high expression of cleaved Caspase-3 protein, and it can modulate ATPase and nitric oxide synthase (NOS) levels, oxidative stress and neurotransmitter disturbance. In summary, PIMPC acts on multiple targets to relieve the learning and memory impairment of AD rats induced by Aβ/Cu2+.

ImmunoPET imaging of amyloid-beta in a rat model of Alzheimer’s disease with a bispecific, brain-penetrating fusion protein

BackgroundHijacking the transferrin receptor (TfR) is an effective strategy to transport amyloid-beta (Aβ) immuno-positron emission tomography (immunoPET) ligands across the blood–brain barrier (BBB). Such ligands are more sensitive and specific than small-molecule ligands at detecting Aβ pathology in mouse models of Alzheimer’s disease (AD). This study aimed to determine if this strategy would be as sensitive in rats and to assess how TfR affinity affects BBB transport of bispecific immunoPET radioligands.MethodsTwo affinity variants of the rat TfR antibody, OX26, were chemically conjugated to a F(ab′)2 fragment of the anti-Aβ antibody, bapineuzumab (Bapi), to generate two bispecific fusion proteins: OX265-F(ab′)2-Bapi and OX2676-F(ab′)2-Bapi. Pharmacokinetic analyses were performed 4 h and 70 h post-injection of radioiodinated fusion proteins in wild-type (WT) rats. [124I]I-OX265-F(ab′)2-Bapi was administered to TgF344-AD and WT rats for in vivo PET imaging. Ex vivo distribution of injected [124I]I-OX265-F(ab′)2-Bapi and Aβ pathology were assessed.ResultsMore [125I]I-OX265-F(ab′)2-Bapi was taken up into the brain 4 h post-administration than [124I]I-OX2676-F(ab′)2-Bapi. [124I]I-OX265-F(ab′)2-Bapi PET visualized Aβ pathology with significantly higher signals in the TgF344-AD rats than in the WT littermates without Aβ pathology. The PET signals significantly correlated with Aβ levels in AD animals.ConclusionAffinity to TfR affects how efficiently a TfR-targeting bispecific fusion protein will cross the BBB, such that the higher-affinity bispecific fusion protein crossed the BBB more efficiently. Furthermore, bispecific immunoPET imaging of brain Aβ pathology using TfR-mediated transport provides good imaging contrast between TgF344-AD and WT rats, suggesting that this immunoPET strategy has the potential to be translated to higher species.

A Comparative Study of Serum Pharmacochemistry of Kai-Xin-San in Normal and AD Rats Using UPLC-LTQ-Orbitrap-MS.

Kai-Xin-San (KXS) is a classic formula for the treatment of Alzheimer's disease (AD). KXS has been widely used to treat emotional diseases; however, its active components remain unknown. There have been some reports about the efficacy and metabolic analysis of KXS, which are mainly based on studying normal animals. The current work first established an AD rat model by injecting D-galactose into the abdominal cavity and injecting Aβ25-35 into the hippocampus on both sides, followed by intragastric administration of KXS for a consecutive week; then, the analytical method for ethanol extraction from the serum of normal and model rats was developed using UPLC-LTQ-Orbitrap-MS; finally, the transitional components in the blood were systematically compared and analyzed by multivariate statistical analysis. A total of 36 components of KXS were identified in the rat serum of the normal group, including 24 prototype components (including ginsenosides, triterpenoid acids of Poria cocos, polygala saponins, polygala xanthones and polygala ester) and 13 metabolites (including desugar, hydration and oxidation products of ginsenosides, triterpenoid acid hydroxylation, deoxygenation, demethylation, desaturation, and glycine-conjugated products of Poria cocos). Twenty KXS-relevant components were detected in the rat serum of the model group, including 11 prototypes and 9 metabolites. The normal group and the model group shared 12 common components, including 9 prototypes and 3 metabolites. The intestinal microecological balance of the model rats probably was destroyed, affecting the absorption/metabolism of saponins by the body, which resulted in fewer transitional components in the model group. This study reflected the drug-body interaction from an objective and accurate perspective, offering references and insights for elucidating the basis of active components and mechanism of action of KXS for treating AD.

Measurement of Protein Synthesis Rate in Rat by [11C]Leucine PET Imaging: Application to the TgF344-AD Model of Alzheimer’s Disease

Long-term memory requires stable protein synthesis and is altered in Alzheimer’s disease (AD). This study aimed to implement a method to measure the cerebral protein synthesis rate (PSR) with [11C]leucine PET in vivo in rats and evaluate potential PSR alterations longitudinally (6, 12 and 18 months old) in the TgF344-AD rat model of AD. Wistar, wild-type (WT) and TgF344-AD rats (TG) were scanned for 60 min with [11C]leucine. Arterial blood activity was monitored online and with discrete whole blood and plasma samples by γ-counting in Wistar rats, WT (n = 4) and TG (n = 5). Unlabelled amino acids were measured in plasma. The sensitivity of [11C]leucine PET to measure alterations in PSR was assessed in Wistar rats by injection of PSR inhibitor anisomycin before PET acquisition. Anisomycin administration significantly reduced the net uptake rate constant (Kcplx) of [11C]leucine and PSR, proving the suitability of the method. For the longitudinal study, averaged population-based input functions were used to calculate PSR. We found a significant genotype effect on PSR (decrease in TG vs WT) only in the globus pallidus. This study suggests that [11C]leucine PET is sensitive enough to measure brain PSR in rat but that cross-sectional design with individual input function should be preferred.

Cationic biopolymer decorated Asiatic Acid and Centella asiatica extract incorporated liposomes for treating early-stage Alzheimer's disease: An In-vitro and In-vivo investigation.

Background:Asiatic acid (AA) is a naturally occurring triterpenoid derivative of Centella asiatica (CA) with neuroprotective effect.The study aimed to design an ideal oral drug delivery system to treat Alzheimer's disease (AD) and develop chitosan-embedded liposomes comprising an extract of CA (CLCAE) and compare them with the chitosan-coated liposomes of asiatic acid (CLAA) for oral delivery to treat the initial phases of AD. Methods:The solvent evaporation technique was used to develop CLCAE and CLAA, optimised with the experiment's design, and was further evaluated. Results:Nuclear magnetic resonance (NMR) studies confirmed coating with chitosan. Transmission electron microscopy(TEM) and atomic force microscopy (AFM) indicated the successful formation of CLCAE and CLAA. Differential scanning colorimetry (DSC) confirmed the drug-phospholipid complex. Furthermore, the rate of in vitrorelease of CLCAE and CLAA was found to be 69.43±0.3 % and 85.3±0.3 %, respectively, in 24 h. Ex vivopermeation of CLCAE and CLAA was found to be 48±0.3 % and 78±0.3 %, respectively. In the Alcl3-induced AD model in rats, disease progression was confirmed by Y-maze, the preliminary histopathology evaluation showed significantly higher efficacy of the prepared liposomes (CLCAE and CLAA) compared to the Centella asiatica extract (CAE) and they were found to have equivalent efficacy to the standard drug (rivastigmine tartrate). The considerable increase in pharmacodynamic parameters in terms of neuronal count in the CLAA group indicated the protective role against Alcl3 toxicity and was also confirmed by assessing acetylcholine (Ach) levels. The pharmacokinetic study, such as C max, T max, and area under curve (AUC) parameters, proved an increase in AA bioavailability in the form of CLAA compared to the pure AA and CLCAE forms. Conclusion:The preclinical study suggested that CLAA was found to have better stability and an ideal oral drug delivery system to treat AD.

Intranasal interferon-beta as a promising alternative for the treatment of Alzheimer's disease

Deterioration in cognitive abilities, especially memory, is characteristic of Alzheimer's disease (AD), a type of neurodegenerative disease. AD's pathological lesions include intracellular neurofibrillary tangles and extracellular amyloid-β plaques. So far, many efforts have been made to find a cure for AD, but there are still no effective pharmacotherapeutic options that relieve the symptoms and enhance the life quality of AD patients. The intranasal (IN) route has been previously used to treat a wide variety of central nervous system disorders as it is a direct, non-invasive method for delivering drugs to the brain. Our prior in vivo preclinical research employing a rat model of AD revealed that intranasally administered interferon-beta (IFNβ) exhibited pro-cognitive and protective benefits. Therefore, we hypothesize that IN administration of IFNβ can be an effective and promising strategy to slow down cognitive decline in AD patients at least partly by reducing amyloid deposition and tau hyperphosphorylated protein accumulation, promoting anti-inflammatory response and anti-apoptotic pathways, increasing neurotrophic factor expression, activating mitochondrial biogenesis, modulating neurogenesis, and improving cerebral glucose metabolism.

Blockade of Type 2A Protein Phosphatase Signaling Attenuates Complement C1q-Mediated Microglial Phagocytosis of Glutamatergic Synapses Induced by Amyloid Fibrils.

We previously reported the critical involvement of metabotropic GluR1 (mGluR1) signaling in complement C1q-dependent microglial phagocytosis of glutamatergic synapses in a rat model of Alzheimer's disease (AD) injected with amyloid fibrils. Here, we explored the role of type 2A protein phosphatase (type 2A PPase), a key enzyme downstream of mGluR1 signaling, in the pathogenesis of AD in rats. Significant local upregulation of PP2A expression was observed in the hippocampal CA1 after bilateral microinjection of amyloid-beta (Aβ1-40) fibrils. Amyloid fibrils induced remarkable dephosphorylation of pFMRP (fragile X mental retardation protein) and C1q upregulation in hippocampal glutamatergic synapses, which was ameliorated by microinjection of type 2A PPase inhibitor okadaic acid (OA). Microinjection of OA further attenuated the microglial phagocytosis of glutamatergic synapses, recovered the hippocampal glutamatergic transmission, and improved the performance in Morris water maze test. These findings demonstrated that dysfunction of type 2A PPase signaling contributed to complement C1q-dependent microglial phagocytosis of glutamatergic synapses and the cognitive impairments in the rat model of AD.

Brain Homogenate of a Rat Model of Alzheimer's Disease Modifies the Secretome of 3D Cultured Periodontal Ligament Stem Cells: A Potential Neuroregenerative Therapy.

Alzheimer's disease (AD) is a progressive neurodegenerative disease leading to neuronal cell death and manifested by cognitive disorders and behavioral impairment. Mesenchymal stem cells (MSCs) are one of the most promising candidates to stimulate neuroregeneration and prevent disease progression. Optimization of MSC culturing protocols is a key strategy to increase the therapeutic potential of the secretome. Here, we investigated the effect of brain homogenate of a rat model of AD (BH-AD) on the enhancement of protein secretion in the secretome of periodontal ligament stem cells (PDLSCs) when cultured in a 3D environment. Moreover, the effect of this modified secretome was examined on neural cells to study the impact of the conditioned medium (CM) on stimulation of regeneration or immunomodulation in AD. PDLSCs were isolated and characterized. Then, the spheroids of PDLSCs were generated in a modified 3D culture plate. PDLSCs-derived CM was prepared in the presence of BH-AD (PDLSCs-HCM) and the absence of it (PDLSCs-CM). The viability of C6 glioma cells was assessed after exposure to different concentrations of both CMs. Then, a proteomic analysis was performed on the CMs. Differentiation into adipocytes and high expression of MSCs markers verified the precise isolation of PDLSCs. The PDLSC spheroids were formed after 7 days of 3D culturing, and their viability was confirmed. The effect of CMs on C6 glioma cell viability showed that both CMs at low concentrations (> 20 mg/mL) had no cytotoxic effect on C6 neural cells. The results showed that PDLSCs-HCM contains higher concentrations of proteins compared to PDLSCs-CM, including Src-homology 2 domain (SH2)-containing PTPs (SHP-1) and muscle glycogen phosphorylase (PYGM) proteins. SHP-1 has a role in nerve regeneration, and PYGM is involved in glycogen metabolism. The modified secretome derived from 3D cultured spheroids of PDLSCs treated by BH-AD as a reservoir of regenerating neural factors can serve as a potential source for AD treatment.

Synaptic loss and gliosis in the nucleus tractus solitarii with streptozotocin-induced Alzheimer’s disease

Obstructive sleep apnea is highly prevalent in Alzheimer’s disease (AD). However, brainstem centers controlling respiration have received little attention in AD research, and mechanisms behind respiratory dysfunction in AD are not understood. The nucleus tractus solitarii (nTS) is an important brainstem center for respiratory control and chemoreflex function. Alterations of nTS integrity, like those shown in AD patients, likely affect neuronal processing and adequate control of breathing. We used the streptozotocin-induced rat model of AD (STZ-AD) to analyze cellular changes in the nTS that corroborate previously documented respiratory dysfunction. We used 2 common dosages of STZ (2 and 3 mg/kg STZ) for model induction and evaluated the early impact on cell populations in the nTS. The hippocampus served as control region to identify site-specific effects of STZ. There was significant atrophy in the caudal nTS of the 3 mg/kg STZ-AD group only, an area known to integrate chemoafferent information. Also, the hippocampus had significant atrophy with the highest STZ dosage tested. Both STZ-AD groups showed respiratory dysfunction along with multiple indices for astroglial and microglial activation. These changes were primarily located in the caudal and intermediate nTS. While there was no change of astrocytes in the hippocampus, microglial activation was accompanied by a reduction in synaptic density. Together, our data demonstrate that STZ-AD induces site-specific effects on all major cell types, primarily in the caudal/intermediate nTS. Both STZ dosages used in this study produced a similar outcome and can be used for future studies examining the initial symptoms of STZ-AD.

Moringa oleifera extract and neostigmine confer neuroprotection on aluminium chloride -induced Alzheimer’s disease: Antioxidant and acetylcholinesterase inhibitory activities

Alzheimer’s disease (AD) is a neurological episode associated with the senescence process characterized by neuronal cell death in brain regions and loss of cognition. The study investigate the neuroprotective potentials of Moringa oleifera leaf extract and Neostigmine in a rat model of Alzheimer’s disease induced by Aluminium chloride (AlCl3). A total number of 20 rats weighing 180-240 kg were used for this study and they were grouped into 5 with 4 rats in each group (n=4) labelled A-E. Group A control, received 0.1 mL normal saline (placebo), Group B, received 100 mg/kg of Aluminium chloride, Group C was given Aluminium chloride 100 mg/kg and 200 mg/kg, Group D experimental animals received Aluminium chloride 100 mg/kg and were treated with 400 mg/kg of the extract orally for 21 days, while Group E received the same dose of Alcl3 and 2 mg/kg Neostigmine given intraperitoneal (IP). Thereafter, the rats were sacrificed, and the hippocampi were harvested for histology and histochemical analysis. Our findings revealed visible protective changes in the group treated with the M. oleifera and Neostigmine as the pyramidal cells of CA3 and neurofibrillary tangles which were prominent in the positive control group were resolved. At the end of this study, it was proven that the toxicity induced by Aluminium chloride was reduced by M. oleifera leaf extract and Neostigmine. M. oleifera is a commonly consumed plant therefore the intake should be encouraged.

5-Methyltetrahydrofolate Alleviates Memory Impairment in a Rat Model of Alzheimer's Disease Induced by D-Galactose and Aluminum Chloride.

The effects of 5-methyltetrahydrofolate (5-MTHF) on a rat model of Alzheimer's disease (AD) induced by D-galactose (D-gal) and aluminum chloride (AlCl3) were investigated. Wistar rats were given an i.p. injection of 60 mg/kg D-gal and 10 mg/kg AlCl3 to induce AD and three doses of 1 mg/kg, 5 mg/kg or 10 mg/kg 5-MTHF by oral gavage. A positive control group was treated with 1 mg/kg donepezil by gavage. Morris water maze performance showed that 5 and 10 mg/kg 5-MTHF significantly decreased escape latency and increased the number of platform crossings and time spent in the target quadrant for AD rats. The administration of 10 mg/kg 5-MTHF decreased the brain content of amyloid β-protein 1-42 (Aβ1-42) and phosphorylated Tau protein (p-Tau) and decreased acetylcholinesterase and nitric oxide synthase activities. Superoxide dismutase activity, vascular endothelial growth factor level and glutamate concentration were increased, and malondialdehyde, endothelin-1, interleukin-6, tumor necrosis factor-alpha and nitric oxide decreased. The administration of 10 mg/kg 5-MTHF also increased the expression of disintegrin and metallopeptidase domain 10 mRNA and decreased the expression of β-site amyloid precursor protein cleavage enzyme 1 mRNA. In summary, 5-MTHF alleviates memory impairment in a D-gal- and AlCl3-exposed rat model of AD. The inhibition of Aβ1-42 and p-Tau release, reduced oxidative stress, the regulation of amyloid precursor protein processing and the release of excitatory amino acids and cytokines may be responsible.

Novel therapeutic mechanism of action of metformin and its nanoformulation in Alzheimer's disease and role of AKT/ERK/GSK pathway

IntroductionBrain Insulin-resistance plays a critical role in pathogenesis of Alzheimer's disease (AD). Current study explored the therapeutic mechanism of metformin (insulin sensitizer) and its solid-lipid nanoformulation (SLN) in rat-model of AD. In our study, SLN was prepared using microemulsion method. AD was induced with ICV-Aβ whereas the control-group (sham) received ICV-NS. Treatment arms included, disease-control (no treatment), Metformin (50 mg/kg, 100 mg/kg and 150 mg/kg), SLN-metformin 50 mg/kg and memantine 1.8 mg/kg (positive-control). Animals were tested for cognitive performance (EPM, MWM) after 21 days of therapy and sacrificed. Aβ (1–42), hyperphosphorylated tau, pAKTser473, GSK-3β, p-ERK (ELISA), metformin level(HPLC), neuronal injury score(H&E), Bcl2 and Bax(IHC) was evaluated in isolated brain. In our study, metformin-SLN were of spherical shape (size<200 nm) with 94.08% entrapment efficiency. Metformin was detectable in brain. Compared to sham, the disease-control group showed significantly higher (p ≤ 0.05) memory impairment(MWM and EPM), hyperphosphorylated tau, Aβ(1–42), neuronal-injury, Bax and lower Bcl-2 expression. Treatment with metformin and nanoformulation significantly reverse these parameters. AKT-ERK-GSK3β-Hyperphosphorylated tau pathway was found to be involved in the protective efficacy of metformin. To conclude, both metformin and its SLN were found to be effective as therapeutic agents in AD which act through the AKT-ERK-GSK3β-Hyperphosphorylated tau pathway. We need population based studies to confirm the same.

Autonomic Dysfunction Impairs Baroreflex Function in an Alzheimer's Disease Animal Model.

Alzheimer's disease (AD) patients frequently present with orthostatic hypotension. This inability to reflexively increase blood pressure on standing is a serious health concern and increases the risk of stroke and cardiovascular diseases. Since there are no clear mechanisms for orthostatic hypotension in human AD, the present study assessed the autonomic changes that could explain this comorbidity in an AD animal model. We used the established streptozotocin-induced rat model of AD (STZ-AD), which mimics many hallmark symptoms of sporadic AD in humans. Baroreflex responses were analyzed in anesthetized STZ-AD rats using femoral catheterization for blood pressure and heart rate, and autonomic activity was assessed using specific blockers and splanchnic sympathetic nerve recordings. Expression levels of autonomic receptors at the heart were examined using the western blot technique. Baroreflex function in STZ-AD showed a blunted heart rate (HR) response to low blood pressure challenges, and the maximal sympathetic nerve activity was reduced. Conversely, HR responses to high blood pressure were similar to control, indicating no change in parasympathetic nerve activity. Under resting conditions, autonomic blockade demonstrated a baseline shift to increased sympathetic tone in STZ-AD. Protein expression levels of beta-1 adrenergic receptor and muscarinic acetylcholine receptor M2 in the heart were unchanged. Our study provides the first data on the pathological influence of AD on baroreflex function, which primarily affected the sympathetic nervous system in STZ-AD. These results represent the first mechanisms that may correlate with the orthostatic hypotension in human AD.

GFAP expression levels are associated with brain glucose metabolism in a rat model of Alzheimer’s disease

AbstractBackgroundGlial Fibrillary Acidic Protein (GFAP) is an intermediate filament expressed almost exclusively in astrocytes, and it is usually overexpressed in reactive astrocytes. We have previously shown that astrocytes play a critical role in brain energy metabolism and are significant contributors to the [18F]FDG‐PET signal. The cortex is majorly composed of glial cells, whereas the cerebellum is predominantly composed of neurons. In light of this, whether GFAP levels in the brain tissue are associated with [18F]FDG‐PET signal remains unknown. Thus, we aimed to investigate the associations between cortical and cerebellar GFAP levels with brain glucose metabolism in a rat model of Alzheimer’s disease.MethodsBrain metabolism of ten‐month‐old TgF344‐AD (n=8) and wild‐type (WT,n=6) rats was assessed with [18F]FDG‐PET. Then, GFAP RNA levels were quantified in the frontal cortex (CXF), temporoparietal cortex (CXTP), and cerebellum (CB) using qRT‐PCR. The [18F]FDG‐PET standardized uptake ratio (SUVr) was calculated using pons as the reference region. T‐tests were used to assess the differences between groups in GFAP RNA expression levels and regional brain [18F]FDG‐PET. Comparisons were conducted using t‐statistical analyses at voxel level (RMINC). Differences were considered statistically significant at p&lt;0.05 (t&gt;2).ResultsNo differences between groups were found in the whole brain FDG metabolism or regions of interest (CXF, CXTP, and CB;t(13)&lt;2). At the voxel level, we identified small cortical hypermetabolic clusters in the TgF344‐AD rats (t(13)=5.55, local maxima). The GFAP RNA was increased in the CXTP of TgF344‐AD rats (p=0.001). No significant differences were found between groups in GFAP RNA levels in other brain regions evaluated. Interestingly, we found positive correlations between [18F]FDG‐PET metabolism and the GFAP RNA expression in the CXTP (local maxima, t(13)=8.33;Fig.1a) and CXF (local maxima, t(13)=4.82;Fig.1b). By contrast, [18F]FDG metabolism did not associate with GFAP RNA expression levels in the CB (t(13)&lt;2;Fig.1c).ConclusionGFAP RNA levels were increased in the CXTP of TgF344‐AD rats, which may indicate early astrocyte reactivity. GFAP RNA expression was associated with [18F]FDG metabolism only in cortical regions, suggesting that astrocytes may have major roles in cortical glucose uptake, but not in cerebellum.

18F]TRACK, a PET tracer for imaging of tropomyosin receptor kinases (Trk): efficient radiosynthesis and preliminary evaluation in the TgF344‐AD rat model of Alzheimer’s disease.

AbstractBackgroundA family of tropomyosin receptor kinases (TrkA/B/C) plays important roles in the regulation of neuronal differentiation, growth, and survival via their interactions with neurotrophins. A growing body of literature suggests the downregulation of Trk in many neurodegenerative conditions of the central nervous system (CNS), including Alzheimer’s disease (AD). We recently reported the development of [18F]TRACK, the PET tracers for in vivo imaging of TrkB and its first in‐human study. Here, we wish to report a fully automated GMP‐compliant radiosynthesis of [18F]TRACK at high radiochemical purity (RCP) and molar activity and its preliminary evaluation in wild‐type and a transgenic rat model of AD.MethodRadiosynthesis was performed using Scintomics GRP automated module via copper‐catalyzed 18F‐fluorination of the chiral boron pinacolate precursor. Brain imaging in wild‐type (n = 3) and TgF344‐AD rat models (n = 2) at 23 months was performed on microPET Concord R4 scanner.Result[18F]TRACK was synthesized with a 5.0±1.4 % radiochemical yield not corrected for decay (activity range 95–154 mCi) with &gt;99% RCP and molar activities of 250 ± 75 GBq/µmol (n = 6). The synthesis was fully automated and all batches passed quality control procedures, including chemical purity, sterility and pyrogenicity. The tracer showed moderate brain uptake in wild‐type rats with the highest accumulation in the thalamus (SUVmax = 1.56 ± 0.28, 10 min post‐injection), consistent with the brain regional distribution in humans acquired in a parallel study. Preliminary data suggests lower tracer uptake in TgF344‐AD rat model of AD in thalamus, striatum and frontal cortex compared to wild‐type animals.ConclusionThis study demonstrated the feasibility of the GMP‐compliant production of [18F]TRACK in sufficient doses and molar activities for scanning multiple subjects per day or long range deliveries. Preliminary biodistribution studies showed moderate brain uptake of the tracer with preferential accumulation in the thalamus across species. These findings warrants further studies of Trk brain expression and its implication in neurodegenerative and psychiatric pathologies using [18F]TRACK.