Epigenetic Alterations in Alzheimer’s Disease and Its Therapeutic and Dietary Interventions
Atanu Bhattacharjee, Akula Ramakrishna, Magisetty Obulesu in Phytomedicine and Alzheimer’s Disease, 2020
Aβ itself has been shown to trigger the epigenetic changes. In a murine cerebral endothelial cell model, Aβ induced global DNA hypomethylation and reduced NEP expression, resulting in an increase in Aβ accumulation and deposition (Chen et al. 2009). The tau protein is the major component of the neurofibrillary tangles present in AD. The Tau gene contains differentially methylated binding sites for transcription factors, and it is subjected to complex epigenetic regulations. The binding sites for Sp1, a transcriptional activator, within the Tau gene promoter was shown to be significantly hypermethylated with age, whereas the binding sites for the GC-rich sequence DNA-binding factor (GCF), a repressor of GC-rich promoters, was shown to be significantly hypomethylated with age, suggesting that transcriptional activity of the Tau gene decreased with age in the human cerebral cortex (Tohgi et al. 1999). However no significant differences in promoter methylation of the Tau gene have been observed in the frontal cortex or hippocampus of post-mortem AD samples (Barrachina and Ferrer 2009).
Central nervous system: Adult-onset and psychiatric disorders
Angus Clarke, Alex Murray, Julian Sampson in Harper's Practical Genetic Counselling, 2019
Alzheimer’s disease is the most common dementia of old age, and increased survival makes it a major problem for society as well as for individual families. Certain diagnosis is only possible at autopsy and rests upon the demonstration of large numbers of senile plaques and neurofibrillary tangles in the brains of those affected. A specific locus on chromosome 21 was suggested by the occurrence of Alzheimer’s disease in older Down syndrome patients, and by the location of the gene encoding β-amyloid precursor protein (the major constituent of the senile plaques) on this chromosome. Specific mutations have now been identified in this gene in a few families showing dominant inheritance of early-onset Alzheimer’s disease, while some others show duplications of APP, but in more families the disease is determined by mutations in the presenilin genes (PSEN1 and PSEN2, on chromosomes 14 and 1, respectively).
Fibroblast Growth Factors
Martin Berry, Ann Logan in CNS Injuries: Cellular Responses and Pharmacological Strategies, 2019
In Parkinson’s disease, there is a preferential loss of dopaminergic neurons in the substantia nigra. Immunocytochemical studies of human Parkinsonian brains revealed a loss of FGF-2 in substantia nigra neurons.100,101 Treatment with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as a mouse model for this disease induces lesions of dopaminergic neurons and elevates transcript levels of FGF-1 and FGF-2 in the striatum but not in the substantia nigra.102 Furthermore, iodinated FGF-2 was shown to be anterogradely transported from the substantia nigra to the striatum.103 FGF seems to be involved in other neurological disorders, too. Brains from Alzheimer patients, for example, display substantially enhanced specific FGF-2 staining of neurons and astrocytes.104 In Alzheimer’s disease, neurofibrillary tangles and neuritic plaques are formed in the cortex and hippocampus.105 The neuritic plaques are reported to be dense accumulations of amyloid material derived from the amyloid precursor protein (APP), a membrane-associated glycoprotein.106 Immunocytochemical studies revealed a frequent colocalization and focal concentration of FGF-1 and FGF-2 with APP within neuritic plaques,104,107,108 suggesting a functional relationship of APP and FGFs. Since FGF-2 is associated with the neuritic plaques, locally available FGF-2 might be reduced, leading to neuronal degeneration.109
Conjunctival microcirculation in ocular and systemic microvascular disease
Published in Clinical and Experimental Optometry, 2023
Kofi Asiedu, Arun V Krishnan, Natalie Kwai, Ann Poynten, Maria Markoulli
Previous studies have shown a significant correlation between the blood flow of the bulbar conjunctiva and the cerebral cortex in animals,25,73 indicating the potential use of the conjunctival microcirculation as an indicator of cerebral microcirculation. Alzheimer’s disease is the most prevalent form of dementia among the elderly population.74 The presence of neurofibrillary tangles characterises the pathogenesis of Alzheimer’s disease, mature senile plaques and cell loss in the amygdala and entorhinal cortex.74–76 Evidence from cortical imaging studies in patients with Alzheimer’s disease demonstrated an apparent reduction in cerebral blood flow first in the posterior cingulate and also the precuneus.74,77 As the disease advances, there is a consistent reduction in blood flow in the temporoparietal association cortices and even medial temporal structures.78,79 As the cerebral blood flow in patients with Alzheimer’s disease is consistently reduced compared to age‐matched healthy controls, one can argue that cerebral hypoperfusion may be a risk factor for Alzheimer disease.77
Privileged multi-target directed propargyl-tacrines combining cholinesterase and monoamine oxidase inhibition activities
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Zofia Chrienova, Eugenie Nepovimova, Rudolf Andrys, Rafael Dolezal, Jana Janockova, Lubica Muckova, Lenka Fabova, Ondrej Soukup, Patrik Oleksak, Martin Valis, Jan Korabecny, José Marco-Contelles, Kamil Kuca
Alzheimer’s disease (AD), the most common cause of dementia, is a growing health concern with huge implications for individuals and society. Current estimates suggest that 44 million people with dementia live worldwide. This number is predicted to increase more than triple by 2050 as the population ages, whereas no effective causal therapeutics are available1. The most typical clinical manifestation of AD in the elderly represents insidious and progressive problems associated with episodic memory. The distinctive features of Alzheimer’s pathology are amyloid plaques and neurofibrillary tangles. Amyloid plaques are extracellular accumulations composed of abnormally folded amyloid protein, whereas neurofibrillary tangles are intracellularly lodged paired helical filaments consisting of hyperphosphorylated tau protein. The downstream consequences of these pathological processes include neurodegeneration with synaptic and neuronal loss leading to macroscopic atrophy2.
The aging brain: impact of heavy metal neurotoxicity
Published in Critical Reviews in Toxicology, 2020
Omamuyovwi M. Ijomone, Chibuzor W. Ifenatuoha, Oritoke M. Aluko, Olayemi K. Ijomone, Michael Aschner
The aggregation of dysfunctional β-amyloid proteins (due to the modification caused by oxidative stress) is common in an aging brain. The inability of proteasome, neprilysin, or insulin-degrading enzymes to destroy these altered proteins leads to their buildup which eventually causes neuronal dysfunction and Alzheimer’s disease (Ashraf et al. 2014; Magalingam et al. 2018). Tau protein is also prone to aggregation during normal aging. The aggregation of tau proteins is responsible for the formation of neurofibrillary tangles seen in age-related neurodegenerative diseases (Goedert 2005; Zarkovic et al. 2017). A similar situation is observed with α-synuclein buildups in neurons. This typically occurs in the dopaminergic neuron population during aging and it is associated with Parkinson’s disease (Shi et al. 2017). The aggregation of the oxidatively altered huntingtin protein is associated with Huntington’s disease (Kojer et al. 2019).
Related Knowledge Centers
- Hyperphosphorylation
- Tau Protein
- Biomarker
- Alzheimer's Disease
- Tauopathy
- Phosphorylation
- Microtubule-Associated Protein
- Ubiquitin
- Immunostaining
- Pyramidal Cell