scholarly journals The selective GSK3 inhibitor, SAR502250, displays neuroprotective activity and attenuates behavioral impairments in models of neuropsychiatric symptoms of Alzheimer’s disease in rodents

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Guy Griebel ◽  
Jeanne Stemmelin ◽  
Mati Lopez-Grancha ◽  
Denis Boulay ◽  
Gerald Boquet ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glycogen Synthase ◽  
Neuropsychiatric Symptoms ◽  
Neuronal Cell ◽  
Tau Proteins ◽  
Neuroprotective Activity ◽  
Mild Stress ◽  
Neurotoxic Peptide ◽  
Gsk3 Inhibitor

AbstractGlycogen synthase kinase 3 (GSK3) has been identified as a promising target for the treatment of Alzheimer’s disease (AD), where abnormal activation of this enzyme has been associated with hyperphosphorylation of tau proteins. This study describes the effects of the selective GSK3 inhibitor, SAR502250, in models of neuroprotection and neuropsychiatric symptoms (NPS) associated with AD. In P301L human tau transgenic mice, SAR502250 attenuated tau hyperphosphorylation in the cortex and spinal cord. SAR502250 prevented the increase in neuronal cell death in rat embryonic hippocampal neurons following application of the neurotoxic peptide, Aβ25–35. In behavioral studies, SAR502250 improved the cognitive deficit in aged transgenic APP(SW)/Tau(VLW) mice or in adult mice after infusion of Aβ25–35. It attenuated aggression in the mouse defense test battery and improved depressive-like state of mice in the chronic mild stress procedure after 4 weeks of treatment. Moreover, SAR502250 decreased hyperactivity produced by psychostimulants. In contrast, the drug failed to modify anxiety-related behaviors or sensorimotor gating deficit. This profile confirms the neuroprotective effects of GSK3 inhibitors and suggests an additional potential in the treatment of some NPS associated with AD.

scholarly journals MiR-219 deficiency in Alzheimer’s disease contributes to neurodegeneration and memory dysfunction through post-transcriptional regulation of tau-kinase network

2019 ◽  
Author(s):  
Mercedes Arnes ◽  
Yoon A. Kim ◽  
Jerome Lannes ◽  
Maria E. Alaniz ◽  
Joshua D. Cho ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Entorhinal Cortex ◽  
Glycogen Synthase ◽  
Expression Patterns ◽  
Adult Brain ◽  
Tau Proteins ◽  
Transcriptional Level ◽  
Microrna Target ◽  
Cellular Models

AbstractIntracellular accumulation of hyperphosphorylated misfolded tau proteins is one of the main neuropathological hallmarks in Alzheimer’s disease (AD) and related tauopathies. Hence, knowledge and understanding of disease mechanisms altering tau proteostasis and inducing cytotoxicity is critical. MicroRNAs (miRNAs) are capable of binding to and silencing many target transcripts, providing an additional level of regulation that complements canonical transcriptional pathways. Therefore, observed abnormalities in their expression patterns in neurodegeneration suggest alterations of microRNA-target networks as drivers of cellular dysfunction in the disease. Strikingly, here we have found in autopsy brain tissue that miRNA miR-219 expression levels are decreased in a brain region early affected in AD patients, the entorhinal cortex. Our bioinformatics analysis indicates miR-219 is predicted to target Calcium/calmodulin-dependent protein kinase 2 gamma subunit (CAMK2γ), Tau tubulin kinase 1 (TTBK1) and Glycogen synthase kinase 3 beta (GSK3β), which are all implicated in the generation of abnormal hyperphosphorylated tau. We reveal human proteomic data supporting dysregulation in the levels of predicted miR-219 targets in the entorhinal cortex. In mammalian cellular models, we found that downregulation of miR-219 de-repress synthesis of three tau kinases, CAMK2γ, TTBK1 and GSK3β on the post-transcriptional level resulting in tau phosphorylation and cell toxicity. Finally, we show that deficiency of miR-219 in vivo promotes age dependent neurodegeneration in the adult brain, with enhanced alterations in tau proteostasis, presynaptic terminals and memory impairment. Taken together, our data implicate miRNA dysregulation central to AD etiopathogenesis and suggest potential targets for the treatment of AD and related tauopathies.

Multifunctional Ligands with Glycogen Synthase Kinase 3 Inhibitory Activity as a New Direction in Drug Research for Alzheimer’s Disease

2020 ◽  
Vol 27 ◽  
Author(s):  
Agnieszka Jankowska ◽  
Grzegorz Satała ◽  
Andrzej J. Bojarski ◽  
Maciej Pawłowski ◽  
Grażyna Chłoń-Rzepa
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Models ◽  
Inhibitory Activity ◽  
Glycogen Synthase ◽  
Neuropsychiatric Symptoms ◽  
New Drugs ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Multifunctional Ligands

: Alzheimer’s disease (AD) belongs to the most common forms of dementia that causes a progressive loss of brain cells and leads to memory impairment and decline of other thinking skills. There is yet no effective treatment for AD; hence, the search for new drugs that could improve memory and other cognitive functions is one of the hot research topics worldwide. Scientific efforts are also directed toward combating behavioral and psychological symptoms of dementia, which are an integral part of the disease. Several studies have indicated that glycogen synthase kinase 3 beta (GSK3β) plays a crucial role in the pathogenesis of AD. Moreover, GSK3β inhibition provided beneficial effects on memory improvement in multiple animal models of AD. The present review aimed to update the most recent reports on the discovery of novel multifunctional ligands with GSK3β inhibitory activity as potential drugs for the symptomatic and disease-modifying therapy of AD. Compounds with GSK3β inhibitory activity seem to be an effective pharmacological approach for treating the causes and symptoms of AD as they reduced neuroinflammation and pathological hallmarks in animal models of AD and provided relief from cognitive and neuropsychiatric symptoms. These compounds have the potential to be used as drugs for the treatment of AD, but their precise pharmacological, pharmacokinetic, toxicological, and clinical profiles need to be defined.

scholarly journals Serum Tau Proteins as Potential Biomarkers for the Assessment of Alzheimer’s Disease Progression

2020 ◽  
Vol 21 (14) ◽  
pp. 5007 ◽  
Author(s):  
Eunjoo Nam ◽  
Yeong-Bae Lee ◽  
Cheil Moon ◽  
Keun-A Chang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Neuronal Cell ◽  
Tau Proteins ◽  
Clinical Dementia Rating ◽  
Global Deterioration Scale ◽  
Mild Cognitive Impairment Group ◽  
Tau Mutation ◽  
T Tau

Total tau (t-tau) and phosphorylated tau (p-tau) protein elevations in cerebrospinal fluid (CFS) are well-established hallmarks of Alzheimer’s disease (AD), while the associations of serum t-tau and p-tau levels with AD have been inconsistent across studies. To identify more accessible non-invasive AD biomarkers, we measured serum tau proteins and associations with cognitive function in age-matched controls (AMC, n = 26), mild cognitive impairment group (MCI, n = 30), and mild-AD group (n = 20) according to the Mini-mental State Examination (MMSE), Clinical Dementia Rating (CDR), and Global Deterioration Scale (GDS) scores. Serum t-tau, but not p-tau, was significantly higher in the mild-AD group than AMC subjects (p < 0.05), and there were significant correlations of serum t-tau with MMSE and GDS scores. Receiver operating characteristic (ROC) analysis distinguished mild-AD from AMC subjects with moderate sensitivity and specificity (AUC = 0.675). We speculated that tau proteins in neuronal cell-derived exosomes (NEX) isolated from serum would be more strongly associated with brain tau levels and disease characteristics, as these exosomes can penetrate the blood-brain barrier. Indeed, ELISA and Western blotting indicated that both NEX t-tau and p-tau (S202) were significantly higher in the mild-AD group compared to AMC (p < 0.05) and MCI groups (p < 0.01). In contrast, serum amyloid β (Aβ1–42) was lower in the mild-AD group compared to MCI groups (p < 0.001). During the 4-year follow-up, NEX t-tau and p-tau (S202) levels were correlated with the changes in GDS and MMSE scores. In JNPL3 transgenic (Tg) mice expressing a human tau mutation, t-tau and p-tau expression levels in NEX increased with neuropathological progression, and NEX tau was correlated with tau in brain tissue exosomes (tEX), suggesting that tau proteins reach the circulation via exosomes. Taken together, our data suggest that serum tau proteins, especially NEX tau proteins, are useful biomarkers for monitoring AD progression.

Neurofibrillary tangles and tau phosphorylation

2001 ◽  
Vol 67 ◽  
pp. 81-88 ◽  
Author(s):  
Jean-Pierre Brion ◽  
Brian H. Anderton ◽  
Michéle Authelet ◽  
Rejith Dayanandan ◽  
Karelle Leroy ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Neurofibrillary Tangles ◽  
Glycogen Synthase ◽  
Tau Phosphorylation ◽  
Precursor Protein ◽  
Tau Proteins ◽  
Chromosome 17 ◽  
Transfected Cells

Neurofibrillary tangles (NFTs) are a characteristic neuropathological lesion of Alzheimer's disease (AD). They are composed of a highly-phosphorylated form of the microtubule-associated protein tau. We are investigating the relationship between NFTs and microtubule stability and how tau phosphorylation and function is affected in transgenic models and by co-expression with ϐ-amyloid precursor protein and presenilins. In most NFT-bearing neurons, we observed a strong reduction in acetylated α-tubulin immunoreactivity (a marker of stable microtubules) and a reduction of the in situ hybridization signal for tubulin mRNA. In transfected cells, mutated tau forms (corresponding to tau mutations identified in familial forms of frontotemporal dementias linked to chromosome 17) were less efficient in their ability to sustain microtubule growth. These observations are consistent with the hypothesis that destabilization of the microtubule network is an important mechanism of cell dysfunction in Alzheimer's disease. The glycogen synthase kinase-3 ϐ (GSK-3ϐ) generates many phosphorylated sites on tau. We performed a neuroanatomical study of GSK-3ϐ distribution showing that developmental evolution of GSK-3ϐ compartmentalization in neurons paralleled that of phosphorylated tau. Studies on transfected cells and on cultured neurons showed that GSK-3 ϐ activity controls tau phosphorylation and tau functional interaction with microtubules. Tau phosphorylation was not affected in neurons overexpressing ϐ-amyloid precursor protein. Transgenic mice expressing a human tau isoform and double transgenic animals for tau and mutated presenilin 1 have been generated; a somatodendritic accumulation of phosphorylated transgenic tau proteins, as observed in the pretangle stage in AD, has been observed but NFTs were not found, suggesting that additional factors might be necessary to induce their formation.

scholarly journals Cuscutae Japonicae Semen Ameliorates Memory Dysfunction by Rescuing Synaptic Damage in Alzheimer’s Disease Models

Nutrients ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 2591
Author(s):  
In Gyoung Ju ◽  
Namkwon Kim ◽  
Jin Gyu Choi ◽  
Jong Kil Lee ◽  
Myung Sook Oh
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Caspase 3 ◽  
Glycogen Synthase ◽  
Memory Function ◽  
Synaptic Proteins ◽  
Tau Proteins ◽  
Morris Water Maze Test ◽  
Protective Effects ◽  
Primary Neuronal Culture

Alzheimer’s disease (AD) is the most common type of dementia in the elderly. It is characterized by the accumulation of amyloid-beta (Aβ) and progressive cognitive impairment. To alleviate the symptoms of AD, functional foods and nutrients have been used for centuries. In this study, we investigated whether Cuscutae Japonicae Semen (CJS), a medicinal food traditionally used in East Asia, has effects on memory improvement and synapse protection in AD. We orally administered CJS to 5x familiar AD (5xFAD) transgenic mice and performed the Morris water maze test. The results showed that CJS treatment ameliorated the decline of memory function. Then, we demonstrated that CJS attenuated the degeneration of pre- and post-synaptic proteins in the hippocampi of 5xFAD mice. To demonstrate the effects of CJS in vitro, we treated Aβ in primary neuronal culture with CJS and observed that CJS rescued the loss of functional synapses. The protective effects of CJS on the synapse were due to the inhibition of activated caspase-3 expression. Additionally, CJS inhibited the phosphorylation of glycogen synthase kinase-3β and tau proteins, which contribute to synaptic dysfunction. Taken together, our results suggest that CJS is efficient in alleviating memory loss by rescuing caspase-3-mediated synaptic damage in AD treatment.

scholarly journals The Function and Expression of ATP-Binding Cassette Transporters Proteins in the Alzheimer's Disease

2021 ◽  
Author(s):  
Asli Aykac ◽  
Ahmet Özer Sehirli
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Choroid Plexus ◽  
Abc Transporters ◽  
Amyloid Β ◽  
Neuronal Cell ◽  
Tau Proteins ◽  
Atp Binding ◽  
Aβ Peptide ◽  
Atp Binding Cassette

AbstractDespite many years of research, radical treatment of Alzheimer's disease (AD) has still not been found. Amyloid-β (Aβ) peptide is known to play an important role in the pathogenesis of this disease. AD is characterized by three main changes occurring in the central nervous system: (1) Aβ plaque accumulation that prevents synaptic communication, (2) the accumulation of hyperphosphorylated tau proteins that inhibit the transport of molecules inside neurons, and (3) neuronal cell loss of the limbic system. Mechanisms leading to Aβ accumulation in AD are excessive Aβ production as a result of mutations in amyloid precursor protein or genes, and impairment of clearance of Aβ due to changes in Aβ aggregation properties and/or Aβ removal processes. Human ATP-binding cassette (ABC) transporters are expressed in astrocyte, microglia, neuron, brain capillary endothelial cell, choroid plexus, choroid plexus epithelial cell, and ventricular ependymal cell. ABC transporters have essential detoxification and neuroprotective roles in the brain. The expression and functional changes in ABC transporters contribute to the accumulation of Aβ peptide. In conclusion, the review was aimed to summarize and highlight accumulated evidence in the literature focusing on the changing functions of human ABC transporter members, in AD pathogenesis and progression.

Neuroprotective Effects of Ellagic Acid in Alzheimer's Disease: Focus on Underlying Molecular Mechanisms of Therapeutic Potential

2020 ◽  
Vol 26 ◽  
Author(s):  
Nimra Javaid ◽  
Muhammad Ajmal Shah ◽  
Azhar Rasul ◽  
Zunera Chauhdary ◽  
Uzma Saleem ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Ellagic Acid ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Therapeutic Potential ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Acetylcholinesterase Activity ◽  
Neuroprotective Effects

: Neurodegeneration is a multifactorial process involved the different cytotoxic pathways that lead towards neuronal cell death. Alzheimer’s disease (AD) is a persistent neurodegenerative disorder that normally has a steady onset yet later on it worsens. The documented evidence of AD neuropathology manifested the neuro-inflammation, increased reactive oxygen, nitrogen species and decreased antioxidant protective process; mitochondrial dysfunction as well as increased level of acetylcholinesterase activity. Moreover, enhanced action of proteins leads towards neural apoptosis which have a vital role in the degeneration of neurons. The inability of commercial therapeutic options to treat AD with targeting single mechanism leads the attraction towards organic drugs. Ellagic acid is a dimer of gallic acid, latest studies expressed that ellagic acid can initiate the numerous cell signaling transmission and decrease the progression of disorders, involved in the degeneration of neurons. The influential property of ellagic acid to protect the neurons in neurodegenerative disorders is due to its antioxidant effect, iron chelating and mitochondrial protective effect. The main goal of this review is to critically analyze the molecular mode of action of ellagic acid against neurodegeneration.

Targeting Tau Hyperphosphorylation via Kinase Inhibition: Strategy to Address Alzheimer's Disease

2020 ◽  
Vol 20 (12) ◽  
pp. 1059-1073 ◽  
Author(s):  
Ahmad Abu Turab Naqvi ◽  
Gulam Mustafa Hasan ◽  
Md. Imtaiyaz Hassan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Glycogen Synthase ◽  
Paired Helical Filaments ◽  
Tau Hyperphosphorylation ◽  
Microtubule Stabilization ◽  
Extracellular Signal

Microtubule-associated protein tau is involved in the tubulin binding leading to microtubule stabilization in neuronal cells which is essential for stabilization of neuron cytoskeleton. The regulation of tau activity is accommodated by several kinases which phosphorylate tau protein on specific sites. In pathological conditions, abnormal activity of tau kinases such as glycogen synthase kinase-3 &#946; (GSK3&#946;), cyclin-dependent kinase 5 (CDK5), c-Jun N-terminal kinases (JNKs), extracellular signal-regulated kinase 1 and 2 (ERK1/2) and microtubule affinity regulating kinase (MARK) lead to tau hyperphosphorylation. Hyperphosphorylation of tau protein leads to aggregation of tau into paired helical filaments like structures which are major constituents of neurofibrillary tangles, a hallmark of Alzheimer’s disease. In this review, we discuss various tau protein kinases and their association with tau hyperphosphorylation. We also discuss various strategies and the advancements made in the area of Alzheimer&#039;s disease drug development by designing effective and specific inhibitors for such kinases using traditional in vitro/in vivo methods and state of the art in silico techniques.

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