Brain ischemia as a bridge to Alzheimer’s disease

Alzheimer’s disease (AD; progressive neurodegenerative disorder) is associated with cognitive and functional impairment with accompanying neuropsychiatric symptoms. The available pharmacological treatment is of a symptomatic nature and, as such, it does not modify the cause of AD. The currently used drugs to enhance cognition include an N-methyl-d-aspartate receptor antagonist (memantine) and cholinesterase inhibitors. The PUBMED, Medical Subject Heading and Clinical Trials databases were used for searching relevant data. Novel treatments are focused on already approved drugs for other conditions and also searching for innovative drugs encompassing investigational compounds. Among the approved drugs, we investigated, are intranasal insulin (and other antidiabetic drugs: liraglitude, pioglitazone and metformin), bexarotene (an anti-cancer drug and a retinoid X receptor agonist) or antidepressant drugs (citalopram, escitalopram, sertraline, mirtazapine). The latter, especially when combined with antipsychotics (for instance quetiapine or risperidone), were shown to reduce neuropsychiatric symptoms in AD patients. The former enhanced cognition. Procognitive effects may be also expected with dietary antioxidative and anti-inflammatory supplements—curcumin, myricetin, and resveratrol. Considering a close relationship between brain ischemia and AD, they may also reduce post-brain ischemia neurodegeneration. An investigational compound, CN-105 (a lipoprotein E agonist), has a very good profile in AD preclinical studies, and its clinical trial for postoperative dementia is starting soon.

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Potential Drug Candidates to Treat TRPC6 Channel Deficiencies in the Pathophysiology of Alzheimer’s Disease and Brain Ischemia

Cells ◽

10.3390/cells9112351 ◽

2020 ◽

Vol 9 (11) ◽

pp. 2351 ◽

Cited By ~ 1

Author(s):

Veronika Prikhodko ◽

Daria Chernyuk ◽

Yurii Sysoev ◽

Nikita Zernov ◽

Sergey Okovityi ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebral Ischemia ◽

Brain Ischemia ◽

In Vivo Studies ◽

Potential Drug ◽

Drug Candidates ◽

Chemical Structures ◽

Trpc6 Channel

Alzheimer’s disease and cerebral ischemia are among the many causative neurodegenerative diseases that lead to disabilities in the middle-aged and elderly population. There are no effective disease-preventing therapies for these pathologies. Recent in vitro and in vivo studies have revealed the TRPC6 channel to be a promising molecular target for the development of neuroprotective agents. TRPC6 channel is a non-selective cation plasma membrane channel that is permeable to Ca2+. Its Ca2+-dependent pharmacological effect is associated with the stabilization and protection of excitatory synapses. Downregulation as well as upregulation of TRPC6 channel functions have been observed in Alzheimer’s disease and brain ischemia models. Thus, in order to protect neurons from Alzheimer’s disease and cerebral ischemia, proper TRPC6 channels modulators have to be used. TRPC6 channels modulators are an emerging research field. New chemical structures modulating the activity of TRPC6 channels are being currently discovered. The recent publication of the cryo-EM structure of TRPC6 channels should speed up the discovery process even more. This review summarizes the currently available information about potential drug candidates that may be used as basic structures to develop selective, highly potent TRPC6 channel modulators to treat neurodegenerative disorders, such as Alzheimer’s disease and cerebral ischemia.

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Brain Ischemia Activates β- and γ-Secretase Cleavage of Amyloid Precursor Protein: Significance in Sporadic Alzheimer’s Disease

Molecular Neurobiology ◽

10.1007/s12035-012-8360-z ◽

2012 ◽

Vol 47 (1) ◽

pp. 425-434 ◽

Cited By ~ 63

Author(s):

Ryszard Pluta ◽

Wanda Furmaga-Jabłońska ◽

Ryszard Maciejewski ◽

Marzena Ułamek-Kozioł ◽

Mirosław Jabłoński

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Precursor Protein ◽

Brain Ischemia ◽

Precursor Protein ◽

Sporadic Alzheimer’S Disease

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Sporadic Alzheimer’s Disease Begins as Episodes of Brain Ischemia and Ischemically Dysregulated Alzheimer’s Disease Genes

Molecular Neurobiology ◽

10.1007/s12035-013-8439-1 ◽

2013 ◽

Vol 48 (3) ◽

pp. 500-515 ◽

Cited By ~ 65

Author(s):

Ryszard Pluta ◽

Mirosław Jabłoński ◽

Marzena Ułamek-Kozioł ◽

Janusz Kocki ◽

Judyta Brzozowska ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Brain Ischemia ◽

Disease Genes ◽

Sporadic Alzheimer’S Disease

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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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Palm Oil Tocotrienols and Its Potential Against Alzheimer’s disease and Brain Ischemia

International Journal of Biomedical and Advance Research ◽

10.7439/ijbar.v3i9.741 ◽

2012 ◽

Vol 3 (9) ◽

Author(s):

Ibrahim Musa ◽

Huzwah Khaza'ai ◽

Mohd sokhini Abd mutalib

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Brain Ischemia ◽

Palm Oil

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Participation of Amyloid and Tau Protein in Neuronal Death and Neurodegeneration after Brain Ischemia

International Journal of Molecular Sciences ◽

10.3390/ijms21134599 ◽

2020 ◽

Vol 21 (13) ◽

pp. 4599 ◽

Cited By ~ 1

Author(s):

Ryszard Pluta ◽

Marzena Ułamek-Kozioł ◽

Sławomir Januszewski ◽

Stanisław J. Czuczwar

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Brain Ischemia ◽

Tau Protein ◽

Neuronal Cells ◽

Current Evidence ◽

Amyloid Protein ◽

Protein Precursor ◽

Amyloid Protein Precursor ◽

Related Proteins

Current evidence indicates that postischemic brain injury is associated with the accumulation of folding proteins, such as amyloid and tau protein, in the intra- and extracellular spaces of neuronal cells. In this review, we summarize protein changes associated with Alzheimer’s disease and their gene expression (amyloid protein precursor and tau protein) after brain ischemia, and their roles in the postischemic period. Recent advances in understanding the postischemic mechanisms in development of neurodegeneration have revealed dysregulation of amyloid protein precursor, α-, β- and γ-secretase and tau protein genes. Reduced expression of the α-secretase gene after brain ischemia with recirculation causes neuronal cells to be less resistant to injury. We present the latest data that Alzheimer’s disease-related proteins and their genes play a crucial role in postischemic neurodegeneration. Understanding the underlying processes of linking Alzheimer’s disease-related proteins and their genes in development of postischemic neurodegeneration will provide the most significant goals to date for therapeutic development.

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Brain ischemia with Alzheimer phenotype dysregulates Alzheimer's disease-related proteins

Pharmacological Reports ◽

10.1016/j.pharep.2016.01.006 ◽

2016 ◽

Vol 68 (3) ◽

pp. 582-591 ◽

Cited By ~ 12

Author(s):

Marzena Ułamek-Kozioł ◽

Ryszard Pluta ◽

Anna Bogucka-Kocka ◽

Sławomir Januszewski ◽

Janusz Kocki ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Brain Ischemia ◽

Related Proteins

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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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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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