Post-Ischemic Brain Neurodegeneration in the Form of Alzheimer’s Disease Proteinopathy: Possible Therapeutic Role of Curcumin

For thousands of years, mankind has been using plant extracts or plants themselves as medicinal herbs. Currently, there is a great deal of public interest in naturally occurring medicinal substances that are virtually non-toxic, readily available, and have an impact on well-being and health. It has been noted that dietary curcumin is one of the regulators that may positively influence changes in the brain after ischemia. Curcumin is a natural polyphenolic compound with pleiotropic biological properties. The observed death of pyramidal neurons in the CA1 region of the hippocampus and its atrophy are considered to be typical changes for post-ischemic brain neurodegeneration and for Alzheimer’s disease. Additionally, it has been shown that one of the potential mechanisms of severe neuronal death is the accumulation of neurotoxic amyloid and dysfunctional tau protein after cerebral ischemia. Post-ischemic studies of human and animal brains have shown the presence of amyloid plaques and neurofibrillary tangles. The significant therapeutic feature of curcumin is that it can affect the aging-related cellular proteins, i.e., amyloid and tau protein, preventing their aggregation and insolubility after ischemia. Curcumin also decreases the neurotoxicity of amyloid and tau protein by affecting their structure. Studies in animal models of cerebral ischemia have shown that curcumin reduces infarct volume, brain edema, blood-brain barrier permeability, apoptosis, neuroinflammation, glutamate neurotoxicity, inhibits autophagy and oxidative stress, and improves neurological and behavioral deficits. The available data suggest that curcumin may be a new therapeutic substance in both regenerative medicine and the treatment of neurodegenerative disorders such as post-ischemic neurodegeneration.

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The Many Faces of Post-Ischemic Tau Protein in Brain Neurodegeneration of the Alzheimer’s Disease Type

Cells ◽

10.3390/cells10092213 ◽

2021 ◽

Vol 10 (9) ◽

pp. 2213

Author(s):

Ryszard Pluta ◽

Stanisław J. Czuczwar ◽

Sławomir Januszewski ◽

Mirosław Jabłoński

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Brain Injury ◽

Cerebral Ischemia ◽

Tau Protein ◽

Ischemia Reperfusion ◽

Disease Type ◽

Dependent Manner ◽

Ischemic Brain ◽

The Brain

Recent data suggest that post-ischemic brain neurodegeneration in humans and animals is associated with the modified tau protein in a manner typical of Alzheimer’s disease neuropathology. Pathological changes in the tau protein, at the gene and protein level due to cerebral ischemia, can lead to the development of Alzheimer’s disease-type neuropathology and dementia. Some studies have shown increased tau protein staining and gene expression in neurons following ischemia-reperfusion brain injury. Recent studies have found the tau protein to be associated with oxidative stress, apoptosis, autophagy, excitotoxicity, neuroinflammation, blood-brain barrier permeability, mitochondrial dysfunction, and impaired neuronal function. In this review, we discuss the interrelationship of these phenomena with post-ischemic changes in the tau protein in the brain. The tau protein may be at the intersection of many pathological mechanisms due to severe neuropathological changes in the brain following ischemia. The data indicate that an episode of cerebral ischemia activates the damage and death of neurons in the hippocampus in a tau protein-dependent manner, thus determining a novel and important mechanism for the survival and/or death of neuronal cells following ischemia. In this review, we update our understanding of proteomic and genomic changes in the tau protein in post-ischemic brain injury and present the relationship between the modified tau protein and post-ischemic neuropathology and present a positive correlation between the modified tau protein and a post-ischemic neuropathology that has characteristics of Alzheimer’s disease-type neurodegeneration.

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Neuroprotective and Neurological/Cognitive Enhancement Effects of Curcumin after Brain Ischemia Injury with Alzheimer’s Disease Phenotype

International Journal of Molecular Sciences ◽

10.3390/ijms19124002 ◽

2018 ◽

Vol 19 (12) ◽

pp. 4002 ◽

Cited By ~ 13

Author(s):

Ryszard Pluta ◽

Marzena Ułamek-Kozioł ◽

Stanisław Czuczwar

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Brain Injury ◽

Brain Ischemia ◽

Tau Protein ◽

Protective Action ◽

Ischemic Brain Injury ◽

Disease Phenotype ◽

Ischemic Brain ◽

Ca1 Region

In recent years, ongoing interest in ischemic brain injury research has provided data showing that ischemic episodes are involved in the development of Alzheimer’s disease-like neuropathology. Brain ischemia is the second naturally occurring neuropathology, such as Alzheimer’s disease, which causes the death of neurons in the CA1 region of the hippocampus. In addition, brain ischemia was considered the most effective predictor of the development of full-blown dementia of Alzheimer’s disease phenotype with a debilitating effect on the patient. Recent knowledge on the activation of Alzheimer’s disease-related genes and proteins—e.g., amyloid protein precursor and tau protein—as well as brain ischemia and Alzheimer’s disease neuropathology indicate that similar processes contribute to neuronal death and disintegration of brain tissue in both disorders. Although brain ischemia is one of the main causes of death in the world, there is no effective therapy to improve the structural and functional outcomes of this disorder. In this review, we consider the promising role of the protective action of curcumin after ischemic brain injury. Studies of the pharmacological properties of curcumin after brain ischemia have shown that curcumin has several therapeutic properties that include anti-excitotoxic, anti-oxidant, anti-apoptotic, anti-hyperhomocysteinemia and anti-inflammatory effects, mitochondrial protection, as well as increasing neuronal lifespan and promoting neurogenesis. In addition, curcumin also exerts anti-amyloidogenic effects and affects the brain’s tau protein. These results suggest that curcumin may be able to serve as a potential preventive and therapeutic agent in neurodegenerative brain disorders.

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Effects of Inducing Gamma Oscillations in Hippocampal Subregions DG, CA3, and CA1 on the Potential Alleviation of Alzheimer’s Disease-Related Pathology: Computer Modeling and Simulations

Entropy ◽

10.3390/e21060587 ◽

2019 ◽

Vol 21 (6) ◽

pp. 587

Author(s):

Dariusz Świetlik ◽

Jacek Białowąs ◽

Janusz Moryś ◽

Ilona Klejbor ◽

Aida Kusiak

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Dentate Gyrus ◽

Pyramidal Neurons ◽

Gamma Oscillations ◽

Control Model ◽

Transfer Entropy ◽

Ca1 Region ◽

Pathological Model ◽

The One

The aim of this study was to evaluate the possibility of the gamma oscillation function (40–130 Hz) to reduce Alzheimer’s disease related pathology in a computer model of the hippocampal network dentate gyrus, CA3, and CA1 (DG-CA3-CA1) regions. Methods: Computer simulations were made for a pathological model in which Alzheimer’s disease was simulated by synaptic degradation in the hippocampus. Pathology modeling was based on sequentially turning off the connections with entorhinal cortex layer 2 (EC2) and the dentate gyrus on CA3 pyramidal neurons. Gamma induction modeling consisted of simulating the oscillation provided by the septo-hippocampal pathway with band frequencies from 40–130 Hz. Pathological models with and without gamma induction were compared with a control. Results: In the hippocampal regions of DG, CA3, and CA1, and jointly DG-CA3-CA1 and CA3-CA1, gamma induction resulted in a statistically significant improvement in terms of increased numbers of spikes, spikes per burst, and burst duration as compared with the model simulating Alzheimer’s disease (AD). The positive maximal Lyapunov exponent was negative in both the control model and the one with gamma induction as opposed to the pathological model where it was positive within the DG-CA3-CA1 region. Gamma induction resulted in decreased transfer entropy in accordance with the information flow in DG → CA3 and CA3 → CA1. Conclusions: The results of simulation studies show that inducing gamma oscillations in the hippocampus may reduce Alzheimer’s disease related pathology. Pathologically higher transfer entropy values after gamma induction returned to values comparable to the control model.

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Modifications of tau protein after cerebral ischemia and reperfusion in rats are similar to those occurring in Alzheimer’s disease – Hyperphosphorylation and cleavage of 4- and 3-repeat tau

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x16668889 ◽

2016 ◽

Vol 37 (7) ◽

pp. 2441-2457 ◽

Cited By ~ 15

Author(s):

Hiroki Fujii ◽

Tetsuya Takahashi ◽

Tomoya Mukai ◽

Shigeru Tanaka ◽

Naohisa Hosomi ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebral Ischemia ◽

Tau Protein ◽

Posttranslational Modification ◽

Epidemiological Studies ◽

Ischemia And Reperfusion ◽

Microtubule Stability ◽

Cerebral Ischemia And Reperfusion ◽

Close Relationship

Epidemiological studies have suggested a close relationship between cerebral ischemia and Alzheimer’s disease (AD). To clarify the pathological association of tau dynamics in both diseases, we performed comprehensive studies on the posttranslational modification of tau in cerebral ischemia and reperfusion (I/R) in rats. The present study suggests that both 4-repeat and 3-repeat tau isoforms are hyperphosphorylated in cerebral I/R, similar to the case in AD. The generation of a 60-kDa Asp421-truncated tau in cerebral I/R preceded the emergence of a 17-kDa 3-repeat tau fragment and a 25-kDa 4-repeat tau fragment. The regional redistribution of tau from the neuropil to neuronal perikarya in our stroke model is thought to share similarity with that occurring in AD. In addition, immunofluorescence staining revealed the formation of axonal varicosities in cerebral I/R. Altered tau distribution may influence microtubule stability, disturbances in axonal transport, and the resulting formation of axonal varicosities. The staining profiles of granules in the ischemic cortex that were immunopositive for RD3, RD4, and AT8 in neuronal perikarya and that were argyrophilic on Gallyas-Braak staining were similar to those in AD. These findings suggest that transient cerebral ischemia shares a common pathology with AD, in the modification of tau protein.

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Cross-Talk between Amyloid, Tau Protein and Free Radicals in Post-Ischemic Brain Neurodegeneration in the Form of Alzheimer’s Disease Proteinopathy

Antioxidants ◽

10.3390/antiox11010146 ◽

2022 ◽

Vol 11 (1) ◽

pp. 146

Author(s):

Ryszard Pluta ◽

Jacek Kiś ◽

Sławomir Januszewski ◽

Mirosław Jabłoński ◽

Stanisław J. Czuczwar

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Dna Damage ◽

Free Radicals ◽

Brain Ischemia ◽

Tau Protein ◽

Dna Damage And Repair ◽

Ischemic Brain ◽

Remarkable Progress

Recent years have seen remarkable progress in research into free radicals oxidative stress, particularly in the context of post-ischemic recirculation brain injury. Oxidative stress in post-ischemic tissues violates the integrity of the genome, causing DNA damage, death of neuronal, glial and vascular cells, and impaired neurological outcome after brain ischemia. Indeed, it is now known that DNA damage and repair play a key role in post-stroke white and gray matter remodeling, and restoring the integrity of the blood-brain barrier. This review will present one of the newly characterized mechanisms that emerged with genomic and proteomic development that led to brain ischemia to a new level of post-ischemic neuropathological mechanisms, such as the presence of amyloid plaques and the development of neurofibrillary tangles, which further exacerbate oxidative stress. Finally, we hypothesize that modified amyloid and the tau protein, along with the oxidative stress generated, are new key elements in the vicious circle important in the development of post-ischemic neurodegeneration in a type of Alzheimer’s disease proteinopathy.

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Participation of Amyloid and Tau Protein in Post-Ischemic Neurodegeneration of the Hippocampus of a Nature Identical to Alzheimer's Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22052460 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2460

Author(s):

Ryszard Pluta ◽

Liang Ouyang ◽

Sławomir Januszewski ◽

Yang Li ◽

Stanisław J. Czuczwar

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Tau Protein ◽

Pyramidal Neurons ◽

Subsequent Development ◽

Amyloid Protein ◽

Protein Precursor ◽

Amyloid Protein Precursor ◽

Therapeutic Development ◽

Ca1 Area

Recent evidence suggests that amyloid and tau protein are of vital importance in post-ischemic death of CA1 pyramidal neurons of the hippocampus. In this review, we summarize protein alterations associated with Alzheimer's disease and their gene expression (amyloid protein precursor and tau protein) after cerebral ischemia, as well as their roles in post-ischemic hippocampus neurodegeneration. In recent years, multiple studies aimed to elucidate the post-ischemic processes in the development of hippocampus neurodegeneration. Their findings have revealed the dysregulation of genes for amyloid protein precursor, β-secretase, presenilin 1 and 2, tau protein, autophagy, mitophagy, and apoptosis identical in nature to Alzheimer's disease. Herein, we present the latest data showing that amyloid and tau protein associated with Alzheimer's disease and their genes play a key role in post-ischemic neurodegeneration of the hippocampus with subsequent development of dementia. Therefore, understanding the underlying process for the development of post-ischemic CA1 area neurodegeneration in the hippocampus in conjunction with Alzheimer's disease-related proteins and genes will provide the most important therapeutic development goals to date.

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Brain Ischemia as a Prelude to Alzheimer's Disease

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.636653 ◽

2021 ◽

Vol 13 ◽

Author(s):

Ryszard Pluta ◽

Sławomir Januszewski ◽

Stanisław J. Czuczwar

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Brain Injury ◽

White Matter ◽

Brain Ischemia ◽

Tau Protein ◽

Ischemia Reperfusion ◽

Acute Stage ◽

Ischemic Brain Injury ◽

Ischemic Brain

Transient ischemic brain injury causes massive neuronal death in the hippocampus of both humans and animals. This was accompanied by progressive atrophy of the hippocampus, brain cortex, and white matter lesions. Furthermore, it has been noted that neurodegenerative processes after an episode of ischemia-reperfusion in the brain can continue well-beyond the acute stage. Rarefaction of white matter was significantly increased in animals at 2 years following ischemia. Some rats that survived 2 years after ischemia developed severe brain atrophy with dementia. The profile of post-ischemic brain neurodegeneration shares a commonality with neurodegeneration in Alzheimer's disease. Furthermore, post-ischemic brain injury is associated with the deposition of folding proteins, such as amyloid and tau protein, in the intracellular and extracellular space. Recent studies on post-ischemic brain neurodegeneration have revealed the dysregulation of Alzheimer's disease-associated genes such as amyloid protein precursor, α-secretase, β-secretase, presenilin 1, presenilin 2, and tau protein. The latest data demonstrate that Alzheimer's disease-related proteins and their genes play a key role in the development of post-ischemic brain neurodegeneration with full-blown dementia in disease types such as Alzheimer's. Ongoing interest in the study of brain ischemia has provided evidence showing that ischemia may be involved in the development of the genotype and phenotype of Alzheimer's disease, suggesting that brain ischemia can be considered as a useful model for understanding the mechanisms responsible for the initiation of Alzheimer's disease.

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Shared Genomic and Proteomic Contribution of Amyloid and Tau Protein Characteristic of Alzheimer’s Disease to Brain Ischemia

International Journal of Molecular Sciences ◽

10.3390/ijms21093186 ◽

2020 ◽

Vol 21 (9) ◽

pp. 3186 ◽

Cited By ~ 2

Author(s):

Ryszard Pluta ◽

Marzena Ułamek-Kozioł ◽

Sławomir Januszewski ◽

Stanisław J. Czuczwar

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Brain Injury ◽

Brain Damage ◽

Tau Protein ◽

Ischemic Brain Injury ◽

Amyloid Protein ◽

Protein Precursor ◽

Ischemic Brain ◽

Amyloid Protein Precursor

Post-ischemic brain damage is associated with the deposition of folding proteins such as the amyloid and tau protein in the intra- and extracellular spaces of brain tissue. In this review, we summarize the protein changes associated with Alzheimer’s disease and their gene expression (amyloid protein precursor and tau protein) after ischemia-reperfusion brain injury and their role in the post-ischemic injury. Recent advances in understanding the post-ischemic neuropathology have revealed dysregulation of amyloid protein precursor, α-secretase, β-secretase, presenilin 1 and 2, and tau protein genes after ischemic brain injury. However, reduced expression of the α-secretase in post-ischemic brain causes neurons to be less resistant to injury. In this review, we present the latest evidence that proteins associated with Alzheimer’s disease and their genes play a key role in progressive brain damage due to ischemia and reperfusion, and that an ischemic episode is an essential and leading supplier of proteins and genes associated with Alzheimer’s disease in post-ischemic brain. Understanding the underlying processes of linking Alzheimer’s disease-related proteins and their genes in post-ischemic brain injury with the risk of developing Alzheimer’s disease will provide the most significant goals for therapeutic development to date.

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