Protective effects of a natural product, curcumin, against amyloid β induced mitochondrial and synaptic toxicities in Alzheimer's disease

The purpose of our study was to investigate the protective effects of a natural product—‘curcumin’— in Alzheimer's disease (AD)-like neurons. Although much research has been done in AD, very little has been reported on the effects of curcumin on mitochondrial biogenesis, dynamics, function and synaptic activities. Therefore, the present study investigated the protective effects against amyloid β (Aβ) induced mitochondrial and synaptic toxicities. Using human neuroblastoma (SHSY5Y) cells, curcumin and Aβ, we studied the protective effects of curcumin against Aβ. Further, we also studied preventive (curcumin+Aβ) and intervention (Aβ+curcumin) effects of curcumin against Aβ in SHSY5Y cells. Using real time RT-PCR, immunoblotting and immunofluorescence analysis, we measured mRNA and protein levels of mitochondrial dynamics, mitochondrial biogenesis and synaptic genes. We also assessed mitochondrial function by measuring hydrogen peroxide, lipid peroxidation, cytochrome oxidase activity and mitochondrial ATP. Cell viability was studied using the MTT assay. Aβ was found to impair mitochondrial dynamics, reduce mitochondrial biogenesis and decrease synaptic activity and mitochondrial function. In contrast, curcumin enhanced mitochondrial fusion activity and reduced fission machinery, and increased biogenesis and synaptic proteins. Mitochondrial function and cell viability were elevated in curcumin treated cells. Interestingly, curcumin pre- and post-treated cells incubated with Aβ showed reduced mitochondrial dysfunction, and maintained cell viability and mitochondrial dynamics, mitochondrial biogenesis and synaptic activity. Further, the protective effects of curcumin were stronger in pretreated SHSY5Y cells than in post-treated cells, indicating that curcumin works better in prevention than treatment in AD-like neurons. Our findings suggest that curcumin is a promising drug molecule to treat AD patients.

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Protective effects of BACE1 inhibitory ligand molecules against amyloid beta-induced synaptic and mitochondrial toxicities in Alzheimer’s disease

Human Molecular Genetics ◽

10.1093/hmg/ddz227 ◽

2019 ◽

Vol 29 (1) ◽

pp. 49-69 ◽

Cited By ~ 5

Author(s):

Jangampalli Adi Pradeepkiran ◽

Arubala P Reddy ◽

Xiangling Yin ◽

Maria Manczak ◽

P Hemachandra Reddy

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mitochondrial Dynamics ◽

Mitochondrial Fission ◽

Amyloid Β ◽

Synaptic Activity ◽

Brain State ◽

Potential Candidate ◽

Protective Effects ◽

App Processing

Abstract Amyloid-β (Aβ) peptides are the major drivers of Alzheimer’s disease (AD) pathogenesis, and are formed by successive cleavage of the amyloid precursor protein (APP) by the beta and gamma secretases. Mounting evidence suggests that Aβ and mitochondrial structural and functional abnormalities are critically involved in the loss of synapses and cognitive decline, in patients with AD. In AD brain, state the sequential proteolytic cleavage of APP by beta secretase 1 enzyme (BACE1) and γ-secretase leads to the production and release of Aβ40 and 42. BACE1 expression and activity increased in the brains of AD patients. Structurally, β-secretase has a very large binding site (1000 Å) with fewer hydrophobic domains that makes a challenge to identify the specific targets/binding sites of BACE1. In the present study, we constructed a BACE1 pharmacophore with pepstatin and screened through molecular docking studies. We found one potential candidate (referred as ligand 1) that binds to the key catalytic residues of BACE1 and predicts to inhibit abnormal APP processing and reduce Aβ levels in AD neurons. Using biochemical, molecular, transmission electron microscopy, immunoblotting and immunofluorescence analyses, we studied the protective effects of ligand 1 against Aβ-induced synaptic and mitochondrial toxicities in mouse neuroblastoma (N2a) cells that express mutant APP. We found interaction between ligand 1 and BACE1 and this interaction decreased BACE1 activity, Aβ40 and 42 levels. We also found increased mitochondrial biogenesis, mitochondrial fusion and synaptic activity and reduced mitochondrial fission in ligand 1-treated mutant APP cells. Based on these results, we cautiously conclude that ligand 1 reduces Aβ-induced mitochondrial and synaptic toxicities, and maintains mitochondrial dynamics and neuronal function in AD.

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Epoxyeicosatrienoic acids pretreatment improves amyloid β-induced mitochondrial dysfunction in cultured rat hippocampal astrocytes

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00001.2013 ◽

2014 ◽

Vol 306 (4) ◽

pp. H475-H484 ◽

Cited By ~ 39

Author(s):

Pallabi Sarkar ◽

Ivan Zaja ◽

Martin Bienengraeber ◽

Kevin R. Rarick ◽

Maia Terashvili ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mitochondrial Dysfunction ◽

Rat Brain ◽

Clinical Symptoms ◽

Mitochondrial Dynamics ◽

Amyloid Β ◽

Cellular Respiration ◽

Epoxyeicosatrienoic Acids ◽

Hippocampal Astrocytes

Amyloid-β (Aβ) has long been implicated as a causative protein in Alzheimer's disease. Cellular Aβ accumulation is toxic and causes mitochondrial dysfunction, which precedes clinical symptoms of Alzheimer's disease pathology. In the present study, we explored the possible use of epoxyeicosatrienoic acids (EETs), epoxide metabolites of arachidonic acid, as therapeutic target against Aβ-induced mitochondrial impairment using cultured neonatal hippocampal astrocytes. Inhibition of endogenous EET production by a selective epoxygenase inhibitor, MS-PPOH, caused a greater reduction in mitochondrial membrane potential in the presence of Aβ (1, 10 μM) exposure versus absence of Aβ. MS-PPOH preincubation also aggravated Aβ-induced mitochondrial fragmentation. Preincubation of the cells with either 14,15- or 11,12-EET prevented this mitochondrial depolarization and fragmentation. EET pretreatment also further improved the reduction observed in mitochondrial oxygen consumption in the presence of Aβ. Preincubation of the cells with EETs significantly improved cellular respiration under basal condition and in the presence of the protonophore, carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP). The uncoupling of ATP synthase from the electron transfer chain that occurred in Aβ-treated cells was also prevented by preincubation with EETs. Lastly, cellular reactive oxygen species production, a hallmark of Aβ toxicity, also showed significant reduction in the presence of EETs. We have previously shown that Aβ reduces EET synthesis in rat brain homogenates and cultured hippocampal astrocytes and neurons (Sarkar P, Narayanan J, Harder DR. Differential effect of amyloid beta on the cytochrome P450 epoxygenase activity in rat brain. Neuroscience 194: 241–249, 2011). We conclude that reduction of endogenous EETs may be one of the mechanisms through which Aβ inflicts toxicity and thus supplementing the cells with exogenous EETs improves mitochondrial dynamics and prevents metabolic impairment.

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Isoforsythiaside Attenuates Alzheimer’s Disease via Regulating Mitochondrial Function Through the PI3K/AKT Pathway

International Journal of Molecular Sciences ◽

10.3390/ijms21165687 ◽

2020 ◽

Vol 21 (16) ◽

pp. 5687 ◽

Cited By ~ 2

Author(s):

Chunyue Wang ◽

Jie Hao ◽

Xin Liu ◽

Chenliang Li ◽

Xuyang Yuan ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cell Viability ◽

Mitochondrial Function ◽

B Cell Lymphoma ◽

Akt Pathway ◽

Mitochondrial Apoptosis ◽

Expression Levels ◽

The Brain ◽

Apoptosis Proteins

Improving mitochondrial dysfunction and inhibiting apoptosis has always been regarded as a treatment strategy for Alzheimer’s disease (AD). Isoforsythiaside (IFY), a phenylethanoid glycoside isolated from the dried fruit of Forsythia suspensa, displays antioxidant activity. This study examined the neuroprotective effects of IFY and its underlying mechanisms. In the L-glutamate (L-Glu)-induced apoptosis of HT22 cells, IFY increased cell viability, inhibited mitochondrial apoptosis, and reduced the intracellular levels of reactive oxygen species (ROS), caspase-3, -8 and -9 after 3 h of pretreatment and 12–24 h of co-incubation. In the APPswe/PSEN1dE9 transgenic (APP/PS1) model, IFY reduced the anxiety of mice, improved their memory and cognitive ability, reduced the deposition of beta amyloid (Aβ) plaques in the brain, restrained the phosphorylation of the tau protein to form neurofibrillary tangles, inhibited the level of 4-hydroxynonenal in the brain, and improved phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway-related mitochondrial apoptosis. In Aβ1-42-induced U251 cells, IFY relieved the mitochondrial swelling, crest ruptures and increased their electron density after 3 h of pretreatment and 18–24 h of co-incubation. The improved cell viability and mitochondrial function after IFY incubation was blocked by the synthetic PI3K inhibitor LY294002. Taken together, these results suggest that IFY exerts a protective effect against AD by enhancing the expression levels of anti-apoptosis proteins and reducing the expression levels of pro-apoptosis proteins of B-cell lymphoma-2 (BCL-2) family members though activating the PI3K/AKT pathway.

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The FDA-approved natural product dihydroergocristine reduces the production of the Alzheimer’s disease amyloid-β peptides

Scientific Reports ◽

10.1038/srep16541 ◽

2015 ◽

Vol 5 (1) ◽

Cited By ~ 12

Author(s):

Xiling Lei ◽

Jing Yu ◽

Qi Niu ◽

Jianhua Liu ◽

Patrick C. Fraering ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Natural Product ◽

Amyloid Β

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Hyperactivity Induced by Soluble Amyloid-β Oligomers in the Early Stages of Alzheimer's Disease

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2020.600084 ◽

2021 ◽

Vol 13 ◽

Author(s):

Audrey Hector ◽

Jonathan Brouillette

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Mechanisms ◽

Clinical Symptoms ◽

Epileptiform Activity ◽

Amyloid Β ◽

Gamma Oscillations ◽

Synaptic Activity ◽

Early Stages ◽

The Impact

Soluble amyloid-beta oligomers (Aβo) start to accumulate in the human brain one to two decades before any clinical symptoms of Alzheimer's disease (AD) and are implicated in synapse loss, one of the best predictors of memory decline that characterize the illness. Cognitive impairment in AD was traditionally thought to result from a reduction in synaptic activity which ultimately induces neurodegeneration. More recent evidence indicates that in the early stages of AD synaptic failure is, at least partly, induced by neuronal hyperactivity rather than hypoactivity. Here, we review the growing body of evidence supporting the implication of soluble Aβo on the induction of neuronal hyperactivity in AD animal models, in vitro, and in humans. We then discuss the impact of Aβo-induced hyperactivity on memory performance, cell death, epileptiform activity, gamma oscillations, and slow wave activity. We provide an overview of the cellular and molecular mechanisms that are emerging to explain how Aβo induce neuronal hyperactivity. We conclude by providing an outlook on the impact of hyperactivity for the development of disease-modifying interventions at the onset of AD.

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Mitochondrial Dysfunction and Oxidative Stress in Alzheimer’s Disease

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.617588 ◽

2021 ◽

Vol 13 ◽

Cited By ~ 1

Author(s):

Afzal Misrani ◽

Sidra Tabassum ◽

Li Yang

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mitochondrial Dysfunction ◽

Mitochondrial Function ◽

Mitochondrial Dynamics ◽

Mitochondrial Morphology ◽

Therapeutic Approaches ◽

The Impact ◽

And Oxidative Stress

Mitochondria play a pivotal role in bioenergetics and respiratory functions, which are essential for the numerous biochemical processes underpinning cell viability. Mitochondrial morphology changes rapidly in response to external insults and changes in metabolic status via fission and fusion processes (so-called mitochondrial dynamics) that maintain mitochondrial quality and homeostasis. Damaged mitochondria are removed by a process known as mitophagy, which involves their degradation by a specific autophagosomal pathway. Over the last few years, remarkable efforts have been made to investigate the impact on the pathogenesis of Alzheimer’s disease (AD) of various forms of mitochondrial dysfunction, such as excessive reactive oxygen species (ROS) production, mitochondrial Ca2+ dyshomeostasis, loss of ATP, and defects in mitochondrial dynamics and transport, and mitophagy. Recent research suggests that restoration of mitochondrial function by physical exercise, an antioxidant diet, or therapeutic approaches can delay the onset and slow the progression of AD. In this review, we focus on recent progress that highlights the crucial role of alterations in mitochondrial function and oxidative stress in the pathogenesis of AD, emphasizing a framework of existing and potential therapeutic approaches.

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Altered mitochondrial dynamics and function in APOE4-expressing astrocytes

Cell Death and Disease ◽

10.1038/s41419-020-02776-4 ◽

2020 ◽

Vol 11 (7) ◽

Cited By ~ 2

Author(s):

Eran Schmukler ◽

Shira Solomon ◽

Shira Simonovitch ◽

Yona Goldshmit ◽

Eya Wolfson ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Risk Factor ◽

Transgenic Mice ◽

Mitochondrial Function ◽

Mitochondrial Dynamics ◽

Major Risk Factor ◽

Sporadic Alzheimer’S Disease ◽

Dynamics And Function ◽

And Function

Abstract APOE4 is a major risk factor for sporadic Alzheimer’s disease; however, it is unclear how it exerts its pathological effects. Others and we have previously shown that autophagy is impaired in APOE4 compared to APOE3 astrocytes, and demonstrated differences in the expression of mitochondrial dynamics proteins in brains of APOE3 and APOE4 transgenic mice. Here, we investigated the effect of APOE4 expression on several aspects of mitochondrial function and network dynamics, including fusion, fission, and mitophagy, specifically in astrocytes. We found that APOE3 and APOE4 astrocytes differ in their mitochondrial dynamics, suggesting that the mitochondria of APOE4 astrocytes exhibit reduced fission and mitophagy. APOE4 astrocytes also show impaired mitochondrial function. Importantly, the autophagy inducer rapamycin enhanced mitophagy and improved mitochondrial functioning in APOE4 astrocytes. Collectively, the results demonstrate that APOE4 expression is associated with altered mitochondrial dynamics, which might lead to impaired mitochondrial function in astrocytes. This, in turn, may contribute to the pathological effects of APOE4 in Alzheimer’s disease.

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Suppression of Alzheimer’s Disease-Like Pathology Progression by Mitochondria-Targeted Antioxidant SkQ1: A Transcriptome Profiling Study

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/3984906 ◽

2019 ◽

Vol 2019 ◽

pp. 1-17 ◽

Cited By ~ 5

Author(s):

Natalia A. Stefanova ◽

Nikita I. Ershov ◽

Nataliya G. Kolosova

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mitochondrial Function ◽

Neuronal Loss ◽

Transcriptome Profiling ◽

Synaptic Activity ◽

Oxys Rats ◽

Specific Gene ◽

Rna Seq ◽

Protein Levels

Alzheimer’s disease (AD) is the most common type of dementia, with increasing prevalence and no disease-modifying treatment available yet. There is increasing evidence—from interventions targeting mitochondria—that may shed some light on new strategies for the treatment of AD. Previously, using senescence-accelerated OXYS rats that simulate key characteristics of sporadic AD, we have shown that treatment with mitochondria-targeted antioxidant SkQ1 (plastoquinonyl-decyltriphenylphosphonium) from age 12 to 18 months (that is, during active progression of AD-like pathology)—via improvement of mitochondrial function—prevented the neuronal loss and synaptic damage, enhanced neurotrophic supply, and decreased amyloid-β1–42 protein levels and tau hyperphosphorylation in the hippocampus. In the present study, we continued to explore the mechanisms of the anti-AD effects of SkQ1 in an OXYS rat model through deep RNA sequencing (RNA-seq) and focused upon the cell-specific gene expression alterations in the hippocampus. According to RNA-seq results, OXYS rats had 1,159 differentially expressed genes (DEGs) relative to Wistar rats (control), and 6-month treatment with SkQ1 decreased their number twofold. We found that 10.5% of all DEGs in untreated (control) OXYS rats were associated with mitochondrial function, whereas SkQ1 eliminated differences in the expression of 76% of DEGs (93 from 122 genes). Using transcriptome approaches, we found that the anti-AD effects of SkQ1 are associated with an improvement of the activity of many signaling pathways and intracellular processes. SkQ1 changed the expression of genes in neuronal, glial, and endothelial cells, and these genes are related to mitochondrial function, neurotrophic and synaptic activity, calcium processes, immune and cerebrovascular systems, catabolism, degradation, and apoptosis. Thus, RNA-seq analysis yields a detailed picture of transcriptional changes during the development of AD-like pathology and can point to the molecular and genetic mechanisms of action of the agents (including SkQ1) holding promise for the prevention and treatment of AD.

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