A Look at the Etiology of Alzheimer's Disease based on the Brain Ischemia Model.

Alzheimer's disease (AD) is the frequent form of dementia in the world. Despite over 100 years of research into the causes of AD, including amyloid and tau protein, the research has stalled and has not led to any conclusions. Moreover, numerous projects aimed at finding a cure for AD have also failed to achieve a breakthrough. Thus, the failure of anti-amyloid and anti-tau protein therapy to treat AD significantly influenced the way we began to think about the etiology of the disease. This situation prompted a group of researchers to focus on ischemic brain episodes, which, like AD, mostly present alterations in the hippocampus. In this context, it has been proposed that cerebral ischemic incidents may play a major role in promoting amyloid and tau protein in neurodegeneration in AD. In this review, we summarized the experimental and clinical research conducted over several years on the role of ischemic brain episodes in the development of AD. Studies have shown changes typical of AD in the course of brain neurodegeneration post-ischemia, i.e., progressive brain and hippocampal atrophy, increased amyloid production, and modification of tau protein. In the post-ischemic brain, the diffuse and senile amyloid plaques and the development of neurofibrillary tangles characteristic of AD were revealed. The above data evidently showed that after brain ischemia, there are modifications in protein folding, leading to massive neuronal death and damage to the neuronal network, which triggers dementia with the AD phenotype.

Apoptosis, Autophagy, and Mitophagy Genes in the CA3 Area in an Ischemic Model of Alzheimer's Disease with 2-Year Survival.

Background: Currently, no evidence exists on the expression of apoptosis (CASP3), autophagy (BECN1), and mitophagy (BNIP3) genes in the CA3 area after ischemia with long-term survival. Objective: The goal of the paper was to study changes in above genes expression in CA3 area after ischemia in the period of 6-24 months. Methods: In this study, using quantitative RT-PCR, we present the expression of genes associated with neuronal death in a rat ischemic model of Alzheimer's disease. Results: First time, we demonstrated overexpression of the CASP3 gene in CA3 area after ischemia with survival ranging from 0.5 to 2 years. Overexpression of the CASP3 gene was accompanied by a decrease in the activity level of the BECN1 and BNIP3 genes over a period of 0.5 year. Then, during 1-2 years, BNIP3 gene expression increased significantly and coincided with an increase in CASP3 gene expression. However, BECN1 gene expression was variable, increased significantly at 1 and 2 years and was below control values 1.5 years post-ischemia. Conclusions: Our observations suggest that ischemia with long-term survival induces neuronal death in CA3 through activation of caspase 3 in cooperation with the pro-apoptotic gene BNIP3. This study also suggests that the BNIP3 gene regulates caspase-independent pyramidal neuronal death post-ischemia. Thus, caspase-dependent and -independent death of neuronal cells occur post-ischemia in the CA3 area. Our data suggest new role of the BNIP3 gene in the regulation of post-ischemic neuronal death in CA3. This suggests the involvement of the BNIP3 together with the CASP3 in the CA3 in neuronal death post-ischemia.

Trans- and Cis-Phosphorylated Tau Protein: New Pieces of the Puzzle in the Development of Neurofibrillary Tangles in Post-Ischemic Brain Neurodegeneration of the Alzheimer's Disease-like Type.

Recent evidence indicates that experimental brain ischemia leads to dementia with an Alzheimer's disease-like type phenotype and genotype. Based on the above evidence, it was hypothesized that brain ischemia may contribute to the development of Alzheimer's disease. Brain ischemia and Alzheimer's disease are two diseases characterized by similar changes in the hippocampus that are closely related to memory impairment. Following brain ischemia in animals and humans, the presence of amyloid plaques in the extracellular space and intracellular neurofibrillary tangles was revealed. The phenomenon of tau protein hyperphosphorylation is a similar pathological feature of both post-ischemic brain injury and Alzheimer's disease. In Alzheimer's disease, the phosphorylated Thr231 motif in tau protein has two distinct trans and cis conformations and is the primary site of tau protein phosphorylation in the pre-entanglement cascade and acts as an early precursor of tau protein neuropathology in the form of neurofibrillary tangles. Based on the latest publication, we present a similar mechanism of the formation of neurofibrillary tangles after brain ischemia as in Alzheimer's disease, established on trans- and cis-phosphorylation of tau protein, which ultimately influences the development of tauopathy.

Alpha-, Beta-, and Gamma-Secretase, Amyloid Precursor Protein, and Tau Protein Genes in the Hippocampal CA3 Subfield in an Ischemic Model of Alzheimer's Disease with Survival up to 2 Years.

Background: Understanding the phenomena underlying the non-selective susceptibility to ischemia of pyramidal neurons in the CA3 is important from the point of view of elucidating the mechanisms of memory loss and the development of dementia. Objective: The aim of the study was to investigate changes in genes expression of amyloid precursor protein, its cleaving enzymes and tau protein in CA3 post-ischemia with survival of 12-24 months. Methods: We used an ischemic model of Alzheimer's disease to study the above genes using an RT-PCR protocol. Results: The expression of the amyloid precursor protein gene was above the control values at all times post-ischemia. The expression of the α-secretase gene also exceeded the control values post-ischemia. The expression of the ß-secretase gene increased 12 and 24 months post-ischemia, and 18 months was below control values. Presenilin 1 and 2 genes expression was significantly elevated at all times post-ischemia. Also, tau protein gene expression was significantly elevated throughout the observation period, and peak gene expression was present 12 months post-ischemia. Conclusions: The study suggests that the genes studied are involved in the non-amyloidogenic processing of amyloid precursor protein. Additionally data indicate that brain ischemia with long-term survival causes damage and death of pyramidal neurons in the CA3 area of the hippocampus in a modified tau protein-dependent manner. Thus defining a new and important mechanism of pyramidal neuronal death in the CA3 area post-ischemia. In addition expression of tau protein gene modification after brain ischemia is useful in identifying ischemic mechanisms occurring in Alzheimer's disease.

Ischemia-Reperfusion Programming of Alzheimer's Disease-Related Genes-A New Perspective on Brain Neurodegeneration after Cardiac Arrest.

The article presents the latest data on pathological changes after cerebral ischemia caused by cardiac arrest. The data include amyloid accumulation, tau protein modification, neurodegenerative and cognitive changes, and gene and protein changes associated with Alzheimer's disease. We present the latest data on the dysregulation of genes related to the metabolism of the amyloid protein precursor, tau protein, autophagy, mitophagy, apoptosis, and amyloid and tau protein transport genes. We report that neuronal death after cerebral ischemia due to cardiac arrest may be dependent and independent of caspase. Moreover, neuronal death dependent on amyloid and modified tau protein has been demonstrated. Finally, the results clearly indicate that changes in the expression of the presented genes play an important role in acute and secondary brain damage and the development of post-ischemic brain neurodegeneration with the Alzheimer's disease phenotype. The data indicate that the above genes may be a potential therapeutic target for brain therapy after ischemia due to cardiac arrest. Overall, the studies show that the genes studied represent attractive targets for the development of new therapies to minimize ischemic brain injury and neurological dysfunction. Additionally, amyloid-related genes expression and tau protein gene modification after cerebral ischemia due to cardiac arrest are useful in identifying ischemic mechanisms associated with Alzheimer's disease. Cardiac arrest illustrates the progressive, time- and area-specific development of neuropathology in the brain with the expression of genes responsible for the processing of amyloid protein precursor and the occurrence of tau protein and symptoms of dementia such as those occurring in patients with Alzheimer's disease. By carefully examining the common genetic processes involved in these two diseases, these data may help unravel phenomena associated with the development of Alzheimer's disease and neurodegeneration after cerebral ischemia and may lead future research on Alzheimer's disease or cerebral ischemia in new directions.

LRP1 and RAGE Genes Transporting Amyloid and Tau Protein in the Hippocampal CA3 Area in an Ischemic Model of Alzheimer's Disease with 2-Year Survival.

Explaining changes at the gene level that occur during neurodegeneration in the CA3 area is crucial from the point of view of memory impairment and the development of post-ischemic dementia. An ischemic model of Alzheimer's disease was used to evaluate changes in the expression of genes related to amyloid transport in the CA3 region of the hippocampus after 10 min of brain ischemia with survival of 2, 7 and 30 days and 12, 18 and 24 months. The quantitative reverse transcriptase PCR assay revealed that the expression of the LRP1 and RAGE genes involved in amyloid transport was dysregulated from 2 days to 24 months post-ischemia in the CA3 area of the hippocampus. LRP1 gene expression 2 and 7 days after ischemia was below control values. However, its expression from day 30 to 24 months, survival after an ischemic episode was above control values. RAGE gene expression 2 days after ischemia was below control values, reaching a maximum increase 7 and 30 days post-ischemia. Then, after 12, 18 and 24 months, it was again below the control values. The data indicate that in the CA3 area of the hippocampus, an episode of brain ischemia causes the increased expression of the RAGE gene for 7-30 days during the acute phase and that of LRP1 from 1 to 24 months after ischemia during the chronic stage. In other words, in the early post-ischemic stage, the expression of the gene that transport amyloid to the brain increases (7-30 days). Conversely, in the late post-ischemic stage, amyloid scavenging/cleaning gene activity increases, reducing and/or preventing further neuronal damage or facilitating the healing of damaged sites. This is how the new phenomenon of pyramidal neuronal damage in the CA3 area after ischemia is defined. In summary, post-ischemic modification of the LRP1 and RAGE genes is useful in the study of the ischemic pathways and molecular factors involved in the development of Alzheimer's disease.

Preservation of Biomarkers Associated with Alzheimer's Disease (Amyloid Peptides 1-38, 1-40, 1-42, Tau Protein, Beclin 1) in the Blood of Neonates after Perinatal Asphyxia.

Perinatal asphyxia is a complex disease involving massive death of brain cells in full-term newborns. The most impressive consequence of perinatal asphyxia is a neurodegenerative brain injury called hypoxic-ischemic encephalopathy. Management of newborns after perinatal asphyxia is very difficult due to the lack of measurable biomarkers that would be able to assess the severity of the brain injury in the future, help in the selection of therapy, assess the results of treatment and determine the prognosis for the future. Thus, these limitations make long-term neurodevelopmental outcomes unpredictable during life. Quantifying biomarkers that can detect subclinical changes at a stage where routine brain monitoring or imaging is still mute would be a major advance in the care of neonates with brain neurodegeneration after asphyxia. Understanding the effect of perinatal asphyxia on changes in blood neurodegenerative biomarkers over time, which would be commonly used to assess the severity of postpartum encephalopathy, would be an important step in developing precision in predicting the consequences of brain injuries. We urgently need more accurate early predictive markers to guide clinicians when to use neuroprotective therapy. The needed neurodegenerative biomarkers may represent neuronal pathological changes that can be recognized by new technologies such as genomic and proteomic. Nevertheless, the simultaneous blood tau protein and various amyloid changes with the addition of an autophagy marker beclin 1 after perinatal asphyxia have not been studied. We decided to evaluate serum biomarkers of neuronal injury characteristic for Alzheimer's disease such as amyloid peptides (1-38, 1-40 and 1-42), tau protein and beclin 1, which can predict the progression of brain neurodegeneration in future. In this paper, we report for the first time the significant changes in the above molecules in the blood after asphyxia compared to healthy controls during the 1-7, 8-14 and 15+ days ELISA test.

The Dual Role of Autophagy in Postischemic Brain Neurodegeneration of Alzheimer's Disease Proteinopathy.

Autophagy is a self-defense and self-degrading intracellular system involved in the recycling and elimination of the payload of cytoplasmic redundant components, aggregated or misfolded proteins and intracellular pathogens to maintain cell homeostasis and physiological function. Autophagy is activated in response to metabolic stress or starvation to maintain homeostasis in cells by updating organelles and dysfunctional proteins. In neurodegenerative diseases, such as cerebral ischemia, autophagy is disturbed, e.g., as a result of the pathological accumulation of proteins associated with Alzheimer's disease and their structural changes. Postischemic brain neurodegeneration, such as Alzheimer's disease, is characterized by the accumulation of amyloid and tau protein. After cerebral ischemia, autophagy was found to be activated in neuronal, glial and vascular cells. Some studies have shown the protective properties of autophagy in postischemic brain, while other studies have shown completely opposite properties. Thus, autophagy is now presented as a double-edged sword with possible therapeutic potential in brain ischemia. The exact role and regulatory pathways of autophagy that are involved in cerebral ischemia have not been conclusively elucidated. This review aims to provide a comprehensive look at the advances in the study of autophagy behavior in neuronal, glial and vascular cells for ischemic brain injury. In addition, the importance of autophagy in neurodegeneration after cerebral ischemia has been highlighted. The review also presents the possibility of modulating the autophagy machinery through various compounds on the development of neurodegeneration after cerebral ischemia.

Apitherapy in Post-Ischemic Brain Neurodegeneration of Alzheimer's Disease Proteinopathy: Focus on Honey and Its Flavonoids and Phenolic Acids.

Neurodegeneration of the brain after ischemia is a major cause of severe, long-term disability, dementia, and mortality, which is a global problem. These phenomena are attributed to excitotoxicity, changes in the blood-brain barrier, neuroinflammation, oxidative stress, vasoconstriction, cerebral amyloid angiopathy, amyloid plaques, neurofibrillary tangles, and ultimately neuronal death. In addition, genetic factors such as post-ischemic changes in genetic programming in the expression of amyloid protein precursor, ß-secretase, presenilin-1 and -2, and tau protein play an important role in the irreversible progression of post-ischemic neurodegeneration. Since current treatment is aimed at preventing symptoms such as dementia and disability, the search for causative therapy that would be helpful in preventing and treating post-ischemic neurodegeneration of Alzheimer's disease proteinopathy is ongoing. Numerous studies have shown that the high contents of flavonoids and phenolic acids in honey have antioxidant, anti-inflammatory, anti-apoptotic, anti-amyloid, anti-tau protein, anticholinesterase, serotonergic, and AMPAK activities, influencing signal transmission and neuroprotective effects. Notably, in many preclinical studies, flavonoids and phenolic acids, the main components of honey, were also effective when administered after ischemia, suggesting their possible use in promoting recovery in stroke patients. This review provides new insight into honey's potential to prevent brain ischemia as well as to ameliorate damage in advanced post-ischemic brain neurodegeneration.

Post-Ischemic Permeability of the Blood-Brain Barrier to Amyloid and Platelets as a Factor in the Maturation of Alzheimer's Disease-Type Brain Neurodegeneration.

The aim of this review is to present evidence of the impact of ischemic changes in the blood-brain barrier on the maturation of post-ischemic brain neurodegeneration with features of Alzheimer's disease. Understanding the processes involved in the permeability of the post-ischemic blood-brain barrier during recirculation will provide clinically relevant knowledge regarding the neuropathological changes that ultimately lead to dementia of the Alzheimer's disease type. In this review, we try to distinguish between primary and secondary neuropathological processes during and after ischemia. Therefore, we can observe two hit stages that contribute to Alzheimer's disease development. The onset of ischemic brain pathology includes primary ischemic neuronal damage and death followed by the ischemic injury of the blood-brain barrier with serum leakage of amyloid into the brain tissue, leading to increased ischemic neuronal susceptibility to amyloid neurotoxicity, culminating in the formation of amyloid plaques and ending in full-blown dementia of the Alzheimer's disease type.

Comment on Minich et al. Is Melatonin the "Next Vitamin D"?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements. Nutrients 2022, 14, 3934.

I read an article by Minich D.M. et al. [...].

Melatonin: A Potential Candidate for the Treatment of Experimental and Clinical Perinatal Asphyxia.

Perinatal asphyxia is considered to be one of the major causes of brain neurodegeneration in full-term newborns. The worst consequence of perinatal asphyxia is neurodegenerative brain damage, also known as hypoxic-ischemic encephalopathy. Hypoxic-ischemic encephalopathy is the leading cause of mortality in term newborns. To date, due to the complex mechanisms of brain damage, no effective or causal treatment has been developed that would ensure complete neuroprotection. Although hypothermia is the standard of care for hypoxic-ischemic encephalopathy, it does not affect all changes associated with encephalopathy. Therefore, there is a need to develop effective treatment strategies, namely research into new agents and therapies. In recent years, it has been pointed out that natural compounds with neuroprotective properties, such as melatonin, can be used in the treatment of hypoxic-ischemic encephalopathy. This natural substance with anti-inflammatory, antioxidant, anti-apoptotic and neurofunctional properties has been shown to have pleiotropic prophylactic or therapeutic effects, mainly against experimental brain neurodegeneration in hypoxic-ischemic neonates. Melatonin is a natural neuroprotective hormone, which makes it promising for the treatment of neurodegeneration after asphyxia. It is supposed that melatonin alone or in combination with hypothermia may improve neurological outcomes in infants with hypoxic-ischemic encephalopathy. Melatonin has been shown to be effective in the last 20 years of research, mainly in animals with perinatal asphyxia but, so far, no clinical trials have been performed on a sufficient number of newborns. In this review, we summarize the advantages and limitations of melatonin research in the treatment of experimental and clinical perinatal asphyxia.

The Role of the JAK/STAT Signaling Pathway in the Pathogenesis of Alzheimer's Disease: New Potential Treatment Target.

Alzheimer's disease is characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. However, emerging evidence suggests that neuroinflammation, mediated notably by activated neuroglial cells, neutrophils, and macrophages, also plays an important role in the pathogenesis of Alzheimer's disease. Therefore, understanding the interplay between the nervous and immune systems might be the key to the prevention or delay of Alzheimer's disease progression. One of the most important mechanisms determining gliogenic cell fate is the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway that is influenced by the overactivation of microglia and astrocytes. The JAK/STAT signaling pathway is one of the critical factors that promote neuroinflammation in neurodegenerative diseases such as Alzheimer's disease by initiating innate immunity, orchestrating adaptive immune mechanisms, and finally, constraining neuroinflammatory response. Since a chronic neuroinflammatory environment in the brain is a hallmark of Alzheimer's disease, understanding the process would allow establishing the underlying role of neuroinflammation, then estimating the prognosis of Alzheimer's disease development and finding a new potential treatment target. In this review, we highlight the recent advances in the potential role of JAK/STAT signaling in neurological diseases with a focus on discussing future research directions regarding novel therapeutic approaches and predictive biomarkers for Alzheimer's disease.

Crosstalk between the aging intestinal microflora and the brain in ischemic stroke.

Aging is an inevitable phenomenon experienced by animals and humans, and its intensity varies from one individual to another. Aging has been identified as a risk factor for neurodegenerative disorders by influencing the composition of the gut microbiota, microglia activity and cognitive performance. The microbiota-gut-brain axis is a two-way communication path between the gut microbes and the host brain. The aging intestinal microbiota communicates with the brain through secreted metabolites (neurotransmitters), and this phenomenon leads to the destruction of neuronal cells. Numerous external factors, such as living conditions and internal factors related to the age of the host, affect the condition of the intestinal microflora in the form of dysbiosis. Dysbiosis is defined as changes in the composition and function of the gut microflora that affect the pathogenesis, progress, and response to treatment of a disease entity. Dysbiosis occurs when changes in the composition and function of the microbiota exceed the ability of the microflora and its host to restore equilibrium. Dysbiosis leading to dysfunction of the microbiota-gut-brain axis regulates the development and functioning of the host's nervous, immune, and metabolic systems. Dysbiosis, which causes disturbances in the microbiota-gut-brain axis, is seen with age and with the onset of stroke, and is closely related to the development of risk factors for stroke. The review presents and summarizes the basic elements of the microbiota-gut-brain axis to better understand age-related changes in signaling along the microbiota-gut-brain axis and its dysfunction after stroke. We focused on the relationship between the microbiota-gut-brain axis and aging, emphasizing that all elements of the microbiota-gut-brain axis are subject to age-related changes. We also discuss the interaction between microbiota, microglia and neurons in the aged individuals in the brain after ischemic stroke. Finally, we presented preclinical and clinical studies on the role of the aged microbiota-gut-brain axis in the development of risk factors for stroke and changes in the post-stroke microflora.

Comorbid epilepsy and depression-pharmacokinetic and pharmacodynamic drug interactions.

Background: Major depressive disorder may be encountered in 17% of patients with epilepsy and in patients with drug-resistant epilepsy its prevalence may reach 30%. This indicates that patients with epilepsy may require antidepressant treatment. Purpose: Both pharmacodynamic and pharmacokinetic interactions between antiepileptic (antiseizure) and antidepressant drugs have been reviewed. Also, data on the adverse effects of co-administration of antiepileptic with antidepressant drugs have been added. This article was submitted to Neuropharmacology, a section of the journal Frontiers in Pharmacology. Methods: The review of relevant literature was confined to English-language publications in PUBMED databases. Table data show effects of antidepressants on the seizure susceptibility in experimental animals, results of pharmacodynamic interactions between antiepileptic and antidepressant drugs mainly derived from electroconvulsions in mice, as well as results concerning pharmacokinetic interactions between these drugs in clinical conditions. Conclusion: Antidepressant drugs may exert differentiated effects upon the convulsive threshold which may differ in their acute and chronic administration. Animal data indicate that chronic administration of antidepressants could reduce (mianserin, trazodone) or potentiate the anticonvulsant activity of some antiepileptics (fluoxetine, reboxetine, venlafaxine). There are also examples of neutral interactions (milnacipran).

Acetylated Tau Protein: A New Piece in the Puzzle between Brain Ischemia and Alzheimer's Disease.

Cerebral ischemia in humans and animals is a life-threatening neuropathological event and leads to the development of dementia with the Alzheimer's disease phenotype [...].

Hypothermia after Perinatal Asphyxia Does Not Affect Genes Responsible for Amyloid Production in Neonatal Peripheral Lymphocytes.

In this study, the expression of the genes of the amyloid protein precursor, ß-secretase, presenilin 1 and 2 by RT-PCR in the lymphocytes of newborns after perinatal asphyxia and perinatal asphyxia treated with hypothermia was analyzed at the age of 15-21 days. The relative quantification of Alzheimer's-disease-related genes was first performed by comparing the peripheral lymphocytes of non-asphyxia control versus those with asphyxia or asphyxia with hypothermia. In the newborns who had perinatal asphyxia, the peripheral lymphocytes presented a decreased expression of the amyloid protein precursor and ß-secretase genes. On the other hand, the expression of the presenilin 1 and 2 genes increased in the studied group. The expression of the studied genes in the asphyxia group treated with hypothermia had an identical pattern of changes that were not statistically significant to the asphyxia group. This suggests that the expression of the genes involved in the metabolism of the amyloid protein precursor in the peripheral lymphocytes may be a biomarker of progressive pathological processes in the brain after asphyxia that are not affected by hypothermia. These are the first data in the world showing the role of hypothermia in the gene changes associated with Alzheimer's disease in the peripheral lymphocytes of newborns after asphyxia.