Celastrol Attenuates Learning and Memory Deficits in an Alzheimer’s Disease Rat Model

Alzheimer’s disease (AD) is a chronic progressive neurodegenerative disorder that is associated with learning, memory, and cognitive deficits. Neuroinflammation and synapse loss are involved in the pathology of AD. Diverse measures have been applied to treat AD, but currently, there is no effective treatment. Celastrol (CEL) is a pentacyclic triterpene isolated from Tripterygium wilfordii Hook F that has been shown to enhance cell viability and inhibit amyloid-β production induced by lipopolysaccharides in vitro. In the present study, the protective effect of CEL on Aβ25-35-induced rat model of AD was assessed. Our results showed that CEL administration at a dose of 2 mg/kg/day improved spatial memory in the Morris water maze. Further biochemical analysis showed that CEL treatment of intrahippocampal Aβ25-35-microinjected rats attenuated hippocampal NF-κB activity; inhibited proinflammatory markers, namely, IL-1β, IL-6, and TNF-α; and upregulated anti-inflammatory factors, such as IL-4 and IL-10. Furthermore, CEL upregulated hippocampal neurexin-1β, neuroligin-1, CA1, and PSD95 expression levels, which may improve synaptic function. Simultaneously, CEL also increased glucose metabolism in Aβ25-35-microinjected rats. In conclusion, CEL could exert protective effects against learning and memory decline induced by intrahippocampal Aβ25-35 through anti-inflammation, promote synaptic development, and maintain hippocampal energy metabolism.

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Asiaticoside improves spatial learning and memory abilities of Alzheimer's disease rat model by promoting the expression of PPAγ and inhibiting inflammatory factors

Biomedical Research ◽

10.4066/biomedicalresearch.29-17-2073 ◽

2018 ◽

Vol 29 (5) ◽

Author(s):

Xian Jiang ◽

Siwei Chen ◽

Fang Wang ◽

Daqiang Song ◽

Hong Zhang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Learning And Memory ◽

Spatial Learning ◽

Rat Model ◽

Inflammatory Factors ◽

Spatial Learning And Memory

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Current Progress on Peroxisome Proliferator-activated Receptor Gamma Agonist as an Emerging Therapeutic Approach for the Treatment of Alzheimer's Disease: An Update

Current Neuropharmacology ◽

10.2174/1570159x16666180828100002 ◽

2019 ◽

Vol 17 (3) ◽

pp. 232-246 ◽

Cited By ~ 11

Author(s):

Mahmood Ahmad Khan ◽

Qamre Alam ◽

Absarul Haque ◽

Mohammad Ashafaq ◽

Mohd Jahir Khan ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Lipid Metabolism ◽

Therapeutic Target ◽

Neurodegenerative Disorder ◽

Amyloid Β ◽

Synaptic Function ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Pparγ Agonist

Alzheimer’s disease (AD) is an age-related progressive neurodegenerative disorder, characterized by the deposition of amyloid-β within the brain parenchyma resulting in a significant decline in cognitive functions. The pathophysiological conditions of the disease are recognized by the perturbation of synaptic function, energy and lipid metabolism. In Addition deposition of amyloid plaques also triggers inflammation upon the induction of microglia. Peroxisome proliferatoractivated receptors (PPARs) are ligand-activated transcription factors known to play important role in the regulation of glucose absorption, homeostasis of lipid metabolism and are further known to involved in repressing the expression of genes related to inflammation. Therefore, agonists of this receptor represent an attractive therapeutic target for AD. Recently, both clinical and preclinical studies showed that use of Peroxisome proliferator-activated receptor gamma (PPARγ) agonist improves both learning and memory along with other AD related pathology. Thus, PPARγ signifies a significant new therapeutic target in treating AD. In this review, we have shed some light on the recent progress of how, PPARγ agonist selectively modulated different cellular targets in AD and its amazing potential in the treatment of AD.

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Genistein ameliorates learning and memory deficits in amyloid β(1–40) rat model of Alzheimer’s disease

Neurobiology of Learning and Memory ◽

10.1016/j.nlm.2010.12.001 ◽

2011 ◽

Vol 95 (3) ◽

pp. 270-276 ◽

Cited By ~ 125

Author(s):

Maryam Bagheri ◽

Mohammad-Taghi Joghataei ◽

Simin Mohseni ◽

Mehrdad Roghani

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Learning And Memory ◽

Rat Model ◽

Amyloid Β ◽

Memory Deficits ◽

Model Of Alzheimer’S Disease ◽

Learning And Memory Deficits

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Unraveling the Role of Inwardly Rectifying Potassium Channels in the Hippocampus of an Aβ(1–42)-Infused Rat Model of Alzheimer’s Disease

Biomedicines ◽

10.3390/biomedicines8030058 ◽

2020 ◽

Vol 8 (3) ◽

pp. 58

Author(s):

Enes Akyuz ◽

Chiara Villa ◽

Merve Beker ◽

Birsen Elibol

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Rat Model ◽

Neurodegenerative Disorder ◽

Amyloid Β ◽

Kir Channels ◽

Protein Levels ◽

Model Of Alzheimer’S Disease ◽

Inwardly Rectifying

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with a complex etiology and characterized by cognitive deficits and memory loss. The pathogenesis of AD is not yet completely elucidated, and no curative treatment is currently available. Inwardly rectifying potassium (Kir) channels are important for playing a key role in maintaining the resting membrane potential and controlling cell excitability, being largely expressed in both excitable and non-excitable tissues, including neurons. Accordingly, the aim of the study is to investigate the role of neuronal Kir channels in AD pathophysiology. The mRNA and protein levels of neuronal Kir2.1, Kir3.1, and Kir6.2 were evaluated by real-time PCR and Western blot analysis from the hippocampus of an amyloid-β(Aβ)(1-42)-infused rat model of AD. Extracellular deposition of Aβ was confirmed by both histological Congo red staining and immunofluorescence analysis. Significant decreased mRNA and protein levels of Kir2.1 and Kir6.2 channels were observed in the rat model of AD, whereas no differences were found in Kir3.1 channel levels as compared with controls. Our results provide in vivo evidence that Aβ can modulate the expression of these channels, which may represent novel potential therapeutic targets in the treatment of AD.

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Role of miRNAs in Alzheimer's Disease and Possible Fields of Application

International Journal of Molecular Sciences ◽

10.3390/ijms20163979 ◽

2019 ◽

Vol 20 (16) ◽

pp. 3979 ◽

Cited By ~ 16

Author(s):

Silvestro ◽

Bramanti ◽

Mazzon

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Disorder ◽

Senile Dementia ◽

Amyloid Β ◽

Synaptic Function ◽

In Vivo Studies ◽

Transcriptional Gene Silencing ◽

Amyloid Β Peptide

miRNAs (or microRNAs) are a class of single-stranded RNA molecules, responsible for post-transcriptional gene silencing through binding to the coding region as well as 3’ and 5’ untranslated region of target genes. About 70% of experimentally detectable miRNAs are expressed in the brain and some studies suggest that miRNAs are intimately involved in synaptic function and in specific signals during memory formation. More and more evidence demonstrates the possible involvement of miRNAs in Alzheimer's disease (AD). AD is the most common form of senile dementia, a disease that affects memory and cognitive functions. It is a neurodegenerative disorder characterized by loss of synapses, extracellular amyloid plaques composed of the amyloid-β peptide (Aβ), and intracellular aggregates of hyperphosphorylated TAU protein. This review aims to provide an overview of the in vivo studies of the last 5 years in the literature describing the role of the different miRNAs involved in AD. miRNAs hold huge potential as diagnostic and prognostic biomarkers and, at the same time, their modulation could be a potential therapeutic strategy against AD.

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Heightened β-adrenergic receptor function in the TgF344-AD rat model drives synaptic potentiation and supports learning and memory

10.1101/2020.11.25.398198 ◽

2020 ◽

Author(s):

Anthoni M. Goodman ◽

Bethany M. Langner ◽

Nateka Jackson ◽

Capri Alex ◽

Lori L. McMahon

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Synaptic Plasticity ◽

Dentate Gyrus ◽

Locus Coeruleus ◽

Learning And Memory ◽

Rat Model ◽

Adrenergic Receptors ◽

Synaptic Function ◽

Β Adrenergic Receptors

AbstractThe central noradrenergic (NA) system is critical for maintenance of attention, behavioral flexibility, spatial navigation, and learning and memory, those cognitive functions lost first in early Alzheimer’s disease (AD). In fact, the locus coeruleus (LC), the sole source of norepinephrine (NE) for >90% of the brain, is the first site of pathological tau accumulation in human AD with axon loss throughout forebrain, including hippocampus. The dentate gyrus (DG) is heavily innervated by LC-NA axons, where released norepinephrine (NE) acts on β-adrenergic receptors (ARs) at excitatory synapses from entorhinal cortex (EC) to facilitate long-term synaptic plasticity and memory formation. These synapses dysfunction in early AD prior to cognitive impairment. In the TgF344-AD rat model, degeneration of LC-NA axons in hippocampus recapitulates human AD, providing a preclinical model to investigate synaptic and behavioral consequences. Using immunohistochemistry, Western blot analysis, and brain slice electrophysiology in 6-9 month old wild type and TgF344-AD rats, we discovered that loss of LC-NA axons co-insides with heightened β-AR function at medial perforant path-dentate granule cell synapses (MPP-DCG) that is responsible for the increase in LTP magnitude at these synapses. Furthermore, novel object recognition is facilitated in TgF344-AD rats that requires β-ARs, and pharmacological blockade of β-ARs unmasks a deficit in extinction learning only in TgF344-AD rats, indicating a greater reliance on β-ARs in both behaviors. Thus, a compensatory increase in β-AR function during prodromal AD in TgF344-AD rats heightens synaptic plasticity and preserves some forms of learning and memory.Significance StatementThe locus coeruleus (LC), a brain region located in the brainstem which is responsible for attention and arousal, is damaged first by Alzheimer’s disease pathology. The LC sends axons to hippocampus where released norepinephrine (NE) modulates synaptic function required for learning and memory. How degeneration of LC axons and loss of NE in hippocampus in early AD impacts synaptic function and learning and memory is not well understood despite the importance of LC in cognitive function. We used a transgenic AD rat model with LC axon degeneration mimicking human AD and found that heightened function of β adrenergic receptors in the dentate gyrus increased synaptic plasticity and preserved learning and memory in early stages of the disease.

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Microglia in Alzheimer’s Disease

Current Alzheimer Research ◽

10.2174/1567205017666200212155234 ◽

2020 ◽

Vol 17 (1) ◽

pp. 29-43 ◽

Cited By ~ 3

Author(s):

Patrick Süß ◽

Johannes C.M. Schlachetzki

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Disorder ◽

Current Knowledge ◽

Imaging Techniques ◽

Amyloid Β ◽

Disease Stage ◽

Disease Modifying Therapy ◽

Transcriptomic Signature

: Alzheimer’s Disease (AD) is the most frequent neurodegenerative disorder. Although proteinaceous aggregates of extracellular Amyloid-β (Aβ) and intracellular hyperphosphorylated microtubule- associated tau have long been identified as characteristic neuropathological hallmarks of AD, a disease- modifying therapy against these targets has not been successful. An emerging concept is that microglia, the innate immune cells of the brain, are major players in AD pathogenesis. Microglia are longlived tissue-resident professional phagocytes that survey and rapidly respond to changes in their microenvironment. Subpopulations of microglia cluster around Aβ plaques and adopt a transcriptomic signature specifically linked to neurodegeneration. A plethora of molecules and pathways associated with microglia function and dysfunction has been identified as important players in mediating neurodegeneration. However, whether microglia exert either beneficial or detrimental effects in AD pathology may depend on the disease stage. : In this review, we summarize the current knowledge about the stage-dependent role of microglia in AD, including recent insights from genetic and gene expression profiling studies as well as novel imaging techniques focusing on microglia in human AD pathology and AD mouse models.

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The Involvement of Post-Translational Modifications in Alzheimer's Disease

Current Alzheimer Research ◽

10.2174/1567205014666170505095109 ◽

2018 ◽

Vol 15 (4) ◽

pp. 313-335 ◽

Cited By ~ 19

Author(s):

Serena Marcelli ◽

Massimo Corbo ◽

Filomena Iannuzzi ◽

Lucia Negri ◽

Fabio Blandini ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Protein Modification ◽

Neurodegenerative Disorder ◽

Amyloid Β ◽

Normal Function ◽

Ageing Population ◽

Covalent Bonds ◽

Post Translational Modifications ◽

Related Proteins

Background: Alzheimer's disease (AD) is a neurodegenerative disorder recognized as the most common cause of chronic dementia among the ageing population. AD is histopathologically characterized by progressive loss of neurons and deposits of insoluble proteins, primarily composed of amyloid-β pelaques and neurofibrillary tangles (NFTs). Methods: Several molecular processes contribute to the formation of AD cellular hallmarks. Among them, post-translational modifications (PTMs) represent an attractive mechanism underlying the formation of covalent bonds between chemical groups/peptides to target proteins, which ultimately result modified in their function. Most of the proteins related to AD undergo PTMs. Several recent studies show that AD-related proteins like APP, Aβ, tau, BACE1 undergo post-translational modifications. The effect of PTMs contributes to the normal function of cells, although aberrant protein modification, which may depend on many factors, can drive the onset or support the development of AD. Results: Here we will discuss the effect of several PTMs on the functionality of AD-related proteins potentially contributing to the development of AD pathology. Conclusion: We will consider the role of Ubiquitination, Phosphorylation, SUMOylation, Acetylation and Nitrosylation on specific AD-related proteins and, more interestingly, the possible interactions that may occur between such different PTMs.

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Shotgun lipidomics of liver and brain tissue of Alzheimer’s disease model mice treated with acitretin

Scientific Reports ◽

10.1038/s41598-021-94706-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Anna A. Lauer ◽

Daniel Janitschke ◽

Malena dos Santos Guilherme ◽

Vu Thu Thuy Nguyen ◽

Cornel M. Bachmann ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Disorder ◽

Amyloid Β ◽

Lipid Homeostasis ◽

Medical Surveillance ◽

Shotgun Lipidomics ◽

App Processing ◽

Cognitive Improvement ◽

The Impact

AbstractAlzheimer’s disease (AD) is a very frequent neurodegenerative disorder characterized by an accumulation of amyloid-β (Aβ). Acitretin, a retinoid-derivative and approved treatment for Psoriasis vulgaris, increases non-amyloidogenic Amyloid-Precursor-Protein-(APP)-processing, prevents Aβ-production and elicits cognitive improvement in AD mouse models. As an unintended side effect, acitretin could result in hyperlipidemia. Here, we analyzed the impact of acitretin on the lipidome in brain and liver tissue in the 5xFAD mouse-model. In line with literature, triglycerides were increased in liver accompanied by increased PCaa, plasmalogens and acyl-carnitines, whereas SM-species were decreased. In brain, these effects were partially enhanced or similar but also inverted. While for SM and plasmalogens similar effects were found, PCaa, TAG and acyl-carnitines showed an inverse effect in both tissues. Our findings emphasize, that potential pharmaceuticals to treat AD should be carefully monitored with respect to lipid-homeostasis because APP-processing itself modulates lipid-metabolism and medication might result in further and unexpected changes. Moreover, deducing effects of brain lipid-homeostasis from results obtained for other tissues should be considered cautiously. With respect to acitretin, the increase in brain plasmalogens might display a further positive probability in AD-treatment, while other results, such as decreased SM, indicate the need of medical surveillance for treated patients.

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