The Neuroprotective Effect of L-Carnitine against Glyceraldehyde-Induced Metabolic Impairment: Possible Implications in Alzheimer’s Disease

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive regression and memory loss. Dysfunctions of both glucose metabolism and mitochondrial dynamics have been recognized as the main upstream events of the degenerative processes leading to AD. It has been recently found that correcting cell metabolism by providing alternative substrates can prevent neuronal injury by retaining mitochondrial function and reducing AD marker levels. Here, we induced an AD-like phenotype by using the glycolysis inhibitor glyceraldehyde (GA) and explored whether L-carnitine (4-N-trimethylamino-3-hydroxybutyric acid, LC) could mitigate neuronal damage, both in SH-SY5Y neuroblastoma cells and in rat primary cortical neurons. We have already reported that GA significantly modified AD marker levels; here we demonstrated that GA dramatically compromised cellular bioenergetic status, as revealed by glycolysis and oxygen consumption rate (OCR) evaluation. We found that LC ameliorated cell survival, improved OCR and ATP synthesis, prevented the loss of the mitochondrial membrane potential (Δψm) and reduced the formation of reactive oxygen species (ROS). Of note, the beneficial effect of LC did not rely on the glycolytic pathway rescue. Finally, we noticed that LC significantly reduced the increase in pTau levels induced by GA. Overall, these findings suggest that the use of LC can promote cell survival in the setting of the metabolic impairments commonly observed in AD. Our data suggest that LC may act by maintaining mitochondrial function and by reducing the pTau level.

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Neuropathology of the Brainstem to Mechanistically Understand and to Treat Alzheimer’s Disease

Journal of Clinical Medicine ◽

10.3390/jcm10081555 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1555

Author(s):

Ágoston Patthy ◽

János Murai ◽

János Hanics ◽

Anna Pintér ◽

Péter Zahola ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cortical Neurons ◽

Molecular Mechanisms ◽

Neurodegenerative Disorder ◽

Brain Structures ◽

Specific Information ◽

Cellular Mechanisms ◽

Monoaminergic System ◽

Monoaminergic Neurons

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder as yet without effective therapy. Symptoms of this disorder typically reflect cortical malfunction with local neurohistopathology, which biased investigators to search for focal triggers and molecular mechanisms. Cortex, however, receives massive afferents from caudal brain structures, which do not only convey specific information but powerfully tune ensemble activity. Moreover, there is evidence that the start of AD is subcortical. The brainstem harbors monoamine systems, which establish a dense innervation in both allo- and neocortex. Monoaminergic synapses can co-release neuropeptides either by precisely terminating on cortical neurons or, when being “en passant”, can instigate local volume transmission. Especially due to its early damage, malfunction of the ascending monoaminergic system emerges as an early sign and possible trigger of AD. This review summarizes the involvement and cascaded impairment of brainstem monoaminergic neurons in AD and discusses cellular mechanisms that lead to their dysfunction. We highlight the significance and therapeutic challenges of transmitter co-release in ascending activating system, describe the role and changes of local connections and distant afferents of brainstem nuclei in AD, and summon the rapidly increasing diagnostic window during the last few years.

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Dynamics of Dynamin-Related Protein 1 in Alzheimer’s Disease and Other Neurodegenerative Diseases

Cells ◽

10.3390/cells8090961 ◽

2019 ◽

Vol 8 (9) ◽

pp. 961 ◽

Cited By ~ 28

Author(s):

Darryll Oliver ◽

P. Reddy

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Diseases ◽

Mouse Models ◽

Cell Cultures ◽

Neuronal Damage ◽

Mitochondrial Dynamics ◽

Neurological Diseases ◽

Large Family ◽

Related Protein

The purpose of this article is to highlight the role of dynamin-related protein 1 (Drp1) in abnormal mitochondrial dynamics, mitochondrial fragmentation, autophagy/mitophagy, and neuronal damage in Alzheimer’s disease (AD) and other neurological diseases, including Parkinson’s, Huntington’s, amyotrophic lateral sclerosis, multiple sclerosis, diabetes, and obesity. Dynamin-related protein 1 is one of the evolutionarily highly conserved large family of GTPase proteins. Drp1 is critical for mitochondrial division, size, shape, and distribution throughout the neuron, from cell body to axons, dendrites, and nerve terminals. Several decades of intense research from several groups revealed that Drp1 is enriched at neuronal terminals and involved in synapse formation and synaptic sprouting. Different phosphorylated forms of Drp1 acts as both increased fragmentation and/or increased fusion of mitochondria. Increased levels of Drp1 were found in diseased states and caused excessive fragmentation of mitochondria, leading to mitochondrial dysfunction and neuronal damage. In the last two decades, several Drp1 inhibitors have been developed, including Mdivi-1, Dynasore, P110, and DDQ and their beneficial effects tested using cell cultures and mouse models of neurodegenerative diseases. Recent research using genetic crossing studies revealed that a partial reduction of Drp1 is protective against mutant protein(s)-induced mitochondrial and synaptic toxicities. Based on findings from cell cultures, mouse models and postmortem brains of AD and other neurodegenerative disease, we cautiously conclude that reduced Drp1 is a promising therapeutic target for AD and other neurological diseases.

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Clinical course of Alzheimer’s disease

10.1093/med/9780199569854.003.0002 ◽

2011 ◽

Author(s):

Alberto Lleo ◽

Rafael Blesa

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Daily Living ◽

Clinical Course ◽

Neurodegenerative Disorder ◽

Memory Loss ◽

Remote Memory ◽

Initial Symptom ◽

Delayed Recall ◽

Age Related

• Alzheimer’s disease is an age-related neurodegenerative disorder, with onset usually in late life, characterized by cognitive impairment, a variety of behavioural symptoms, and restrictions in the activities of daily living• The initial symptom is episodic memory loss, in particular in delayed recall of visual and/or verbal material. Immediate and remote memory is usually preserved in early stages...

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Evaluation of the neuroprotective effect of taurine in Alzheimer’s disease using functional molecular imaging

Scientific Reports ◽

10.1038/s41598-020-72755-4 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Se Jong Oh ◽

Hae-June Lee ◽

Ye Ji Jeong ◽

Kyung Rok Nam ◽

Kyung Jun Kang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Imaging ◽

Neurodegenerative Disorder ◽

Therapeutic Potential ◽

Neuroprotective Effect ◽

Treatment Options ◽

Brain Uptake ◽

Positron Emission ◽

Taurine Treatment

Abstract Alzheimer’s disease (AD) is a chronic neurodegenerative disorder and the leading cause of dementia, but therapeutic treatment options are limited. Taurine has been reported to have neuroprotective properties against dementia, including AD. The present study aimed to investigate the treatment effect of taurine in AD mice by functional molecular imaging. To elucidate glutamate alterations by taurine, taurine was administered to 5xFAD transgenic mice from 2 months of age, known to apear amyloid deposition. Then, we performed glutamate positron emission tomography (PET) imaging studies for three groups (wild-type, AD, and taurine-treated AD, n = 5 in each group). As a result, brain uptake in the taurine-treated AD group was 31–40% higher than that in the AD group (cortex: 40%, p < 0.05; striatum: 32%, p < 0.01; hippocampus: 36%, p < 0.01; thalamus: 31%, p > 0.05) and 3–14% lower than that in the WT group (cortex: 10%, p > 0.05; striatum: 15%, p > 0.05; hippocampus: 14%, p > 0.05; thalamus: 3%, p > 0.05). However, we did not observe differences in Aβ pathology between the taurine-treated AD and AD groups in immunohistochemistry experiments. Our results reveal that although taurine treatment did not completely recover the glutamate system, it significantly increased metabolic glutamate receptor type 5 brain uptake. Therefore, taurine has therapeutic potential against AD.

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

Journal of Investigative Medicine ◽

10.1136/jim-2016-000240 ◽

2016 ◽

Vol 64 (8) ◽

pp. 1220-1234 ◽

Cited By ~ 57

Author(s):

P Hemachandra Reddy ◽

Maria Manczak ◽

Xiangling Yin ◽

Mary Catharine Grady ◽

Andrew Mitchell ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cell Viability ◽

Natural Product ◽

Mitochondrial Biogenesis ◽

Mitochondrial Function ◽

Mitochondrial Dynamics ◽

Amyloid Β ◽

Synaptic Activity ◽

Protective Effects

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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The Neuroprotective Effect of the Association of Aquaporin-4/Glutamate Transporter-1 against Alzheimer’s Disease

Neural Plasticity ◽

10.1155/2016/4626593 ◽

2016 ◽

Vol 2016 ◽

pp. 1-8 ◽

Cited By ~ 11

Author(s):

Yu-Long Lan ◽

Shuang Zou ◽

Jian-Jiao Chen ◽

Jie Zhao ◽

Shao Li

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Disorder ◽

Neuroprotective Effect ◽

Ion Homeostasis ◽

Water Channel ◽

Glutamate Transporter ◽

Aquaporin 4 ◽

Normal Brain ◽

Glutamate Transporter 1

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is characterized by memory loss and cognitive dysfunction. Aquaporin-4 (AQP4), which is primarily expressed in astrocytes, is the major water channel expressed in the central nervous system (CNS). This protein plays an important role in water and ion homeostasis in the normal brain and in various brain pathological conditions. Emerging evidence suggests that AQP4 deficiency impairs learning and memory and that this may be related to the expression of glutamate transporter-1 (GLT-1). Moreover, the colocalization of AQP4 and GLT-1 has long been studied in brain tissue; however, far less is known about the potential influence that the AQP4/GLT-1 complex may have on AD. Research on the functional interaction of AQP4 and GLT-1 has been demonstrated to be of great significance in the study of AD. Here, we review the interaction of AQP4 and GLT-1 in astrocytes, which might play a pivotal role in the regulation of distinct cellular responses that involve neuroprotection against AD. The association of AQP4 and GLT-1 could greatly supplement previous research regarding neuroprotection against AD.

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Mitochondrial Deficits With Neural and Social Damage in Early-Stage Alzheimer’s Disease Model Mice

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.748388 ◽

2021 ◽

Vol 13 ◽

Author(s):

Afzal Misrani ◽

Sidra Tabassum ◽

Qingwei Huo ◽

Sumaiya Tabassum ◽

Jinxiang Jiang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Disorder ◽

Early Stage ◽

Mitochondrial Dynamics ◽

Mitochondrial Fission ◽

Neuronal Morphology ◽

Therapeutic Interventions ◽

Early Event ◽

Mitochondrial Morphology

Alzheimer’s disease (AD) is the most common neurodegenerative disorder worldwide. Mitochondrial dysfunction is thought to be an early event in the onset and progression of AD; however, the precise underlying mechanisms remain unclear. In this study, we investigated mitochondrial proteins involved in organelle dynamics, morphology and energy production in the medial prefrontal cortex (mPFC) and hippocampus (HIPP) of young (1∼2 months), adult (4∼5 months) and aged (9∼10, 12∼18 months) APP/PS1 mice. We observed increased levels of mitochondrial fission protein, Drp1, and decreased levels of ATP synthase subunit, ATP5A, leading to abnormal mitochondrial morphology, increased oxidative stress, glial activation, apoptosis, and altered neuronal morphology as early as 4∼5 months of age in APP/PS1 mice. Electrophysiological recordings revealed abnormal miniature excitatory postsynaptic current in the mPFC together with a minor connectivity change between the mPFC and HIPP, correlating with social deficits. These results suggest that abnormal mitochondrial dynamics, which worsen with disease progression, could be a biomarker of early-stage AD. Therapeutic interventions that improve mitochondrial function thus represent a promising approach for slowing the progression or delaying the onset of AD.

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Adaptation to intermittent hypoxia prevents the decrease in cerebral vascular density in rats with experimental Alzheimer’s disease

Regional blood circulation and microcirculation ◽

10.24884/1682-6655-2021-20-2-59-64 ◽

2021 ◽

Vol 20 (2) ◽

pp. 59-64

Author(s):

A. V. Goryacheva ◽

I. V. Barskov ◽

H. F. Downey ◽

Eu. B. Manukhina

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cortical Neurons ◽

Hypoxia Inducible Factor ◽

Memory Loss ◽

Amyloid Peptide ◽

Cresyl Violet ◽

Vascular Density ◽

Endothelial Growth Factor ◽

Cerebral Vascular

Introduction. Patients with Alzheimer’s disease (AD) have reduced cerebral vascular density (VD), which impairs blood flow to neurons and may contribute to progression of AD. Earlier we showed that prior adaptation to intermittent hypobaric hypoxia (IHH) prevented memory loss and degeneration of cortical neurons in rats with experimental AD (EAD). The aim of this study was to test if IHH might prevent EAD-induced vascular rarefaction in rats. Materials and methods. EAD was induced with bilateral injection of neurotoxic beta-amyloid peptide fragment (A) (25–35) into n. basalis magnocellularis. IHH was simulated at a 4,000 m altitude, for 4 hours a day, for 14 days. Brain blood vessels were stained by transcardiac infusion of Indian ink; brain sections were stained with 0.3 % cresyl violet by Nissle method. Vascular density was assessed in the cortex and hippocampus using the Infinity Analysis Software. Results. In the EAD rats, VD was significantly decreased in the hippocampus (13.3±0.9 vs 17.8±1.0 in field of view, FOV, p<0.03) and in the cortex (17.3±1.5 vs 22.3±1.3 in FOV, p<0.03). AIH increased VD in the hippocampus to 27.0±3.5 in FOV (p=0.01) and in cortex to 26.0±1.1 in FOV (p<0.03). In EAD+AIH rats, VD did not differ significantly from the control rats neither in the hippocampus, nor in the cortex. AIH may stimulate angiogenesis through hypoxia inducible factor-1α-mediated expression of vascular endothelial growth factor and/or by increasing expression and activity of antioxidant enzymes. Conclusion. One of the mechanisms of AIH beneficial effect in AD-related neurodegeneration is preserving the capability for compensatory angiogenesis in brain.

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L-Norvaline, a New Therapeutic Agent against Alzheimer’s disease

10.1101/491480 ◽

2018 ◽

Author(s):

Baruh Polis ◽

Kolluru D Srikanth ◽

Vyacheslav Gurevich ◽

Hava Gil-Henn ◽

Abraham O. Samson

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Disorder ◽

Neuroprotective Effect ◽

Quantitative Polymerase Chain Reaction ◽

Biological Pathways ◽

Arginase Activity ◽

Insidious Onset ◽

Polymerase Chain

AbstractAlzheimer’s disease (AD) is a slowly progressive neurodegenerative disorder with an insidious onset. The disease is characterized by cognitive impairment and a distinct pathology with neuritic plaques and neurofibrillary tangles.Growing evidence highlights the role of arginase activity in the manifestation of AD. Upregulation of arginase was shown to contribute to endothelial dysfunction, atherosclerosis, diabetes, and neurodegeneration. Regulation of arginase activity appears to be a promising approach for interfering with the pathogenesis of AD and other metabolic disorders. Therefore, the enzyme represents a novel therapeutic target.Here, we administer an arginase inhibitor L-norvaline to a mouse model of AD. Then, we evaluate the neuroprotective effect of L-norvaline using immunohistochemistry, proteomics, and quantitative polymerase chain reaction assays. Finally, we identify the biological pathways activated by the treatment.Remarkably, we find that L-norvaline treatment reverses the cognitive decline in AD mice. We show the treatment is neuroprotective as indicated by reduced beta-amyloidosis, alleviated microgliosis, and TNFα transcription levels. Moreover, elevated levels of neuroplasticity related protein PSD-95 were detected in the hippocampi of mice treated with L-norvaline. Furthermore, we disclose several biological pathways, which are involved in cell survival and neuroplasticity and are activated by the treatment.Through these modes of action, L-norvaline has the potential to improve the symptoms of AD and even interfere with its pathogenesis. As such, L-norvaline is a promising neuroprotective molecule that might be tailored for the treatment of a range of neurodegenerative disorders.

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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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