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Of brain and bone: The unusual case of Dr. A
Published in Howard J. Rosen, Robert W. Levenson, Neurocase, 2020
J. Narvid, M. L. Gorno-Tempini, A. Slavotinek, S. J. DeArmond, Y. H. Cha, B. L. Miller, K. Rankin
Traditional histopathology staining with hematoxylin and eosin, modified Bielschowsky silver impregnation, and immunostaining with antibodies to b-amyloid revealed multiple foci of neuronal degeneration and loss. Within the frontal lobe, sparse primitive and diffuse neuritic plaques were found. Neurofibrillary tangles were not found in abundance (Figure 2). The cingulate gyrus revealed conspicuous ballooned achromatic neurons and granulovacuolar degeneration (Figure 3). Hippo-campal histopathology revealed changes in both the pyramidal layer as well as the dentate gyrus. In the pyramidal layer, silver-impregnated inclusions, Pick’s bodies, were evident. As well, tau immuno-reactive inclusions were identified. The dentate gyrus showed numerous Pick body inclusion and neuritic plaques (Figure 4). Both the subiculum and hippocampus revealed immunoreactive astrocytes and ‘astrocytic plaques’. In addition, mild focal spongiosis was identified in both the frontal and temporal lobes.
Epigenetic Alterations in Alzheimer’s Disease and Its Therapeutic and Dietary Interventions
Published in Atanu Bhattacharjee, Akula Ramakrishna, Magisetty Obulesu, Phytomedicine and Alzheimer’s Disease, 2020
P. M. Aswathy, C. M. Shafeeque, Moinak Banerjee
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).
Estrogens and dementia: a clinical and epidemiological update
Published in Barry G. Wren, Progress in the Management of the Menopause, 2020
Pathologically, Alzheimer’s disease is manifest by the accumulation of neurofibrillary tangles within vulnerable neurons of the central nervous system and by the abundance of neuritic plaques in the neuropil between nerve cell bodies. A typical neuritic plaque consists of a central core β-amyloid protein surrounded by distended nerve cell processes (neurites). An inflammatory process is suggested by the colocalization within the plaque of microglia and reactive astrocytes, together with cytokines, complement proteins, and acute phase reactants5,6.
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.
Nano-lipidic formulation and therapeutic strategies for Alzheimer’s disease via intranasal route
Published in Journal of Microencapsulation, 2021
Shourya Tripathi, Ujala Gupta, Rewati Raman Ujjwal, Awesh K. Yadav
The most common striking feature that AD has in common with other neurodegenerative diseases is the abnormal folding of proteins. Talking specifically about AD, there is aberrant production of proteins at intracellular and extracellular levels inside the brain. Neurofibrillary tangles are found to increase at the intracellular level whereas amyloid plaques are seen at the extracellular level. There exist many factors behind the origin of AD and one of the widest acclaimed hypothesis behind the abnormal plaque formation is the amyloid cascade hypothesis (Dá Mesquita et al.2016). As for the genetic cause, disease genes that undergo mutation include those encoding presenilin 1 on chromosome 14q24 (PSEN1), presenilin 2 on chromosome 1q42 (PSEN2), and amyloid precursor protein (APP) on chromosome 21q21. These are also known as ‘causative genes’ and are responsible for nearly 5% of AD cases occurring on a totality (Imbimbo et al.2005). Figure 1 portrays the pathophysiology involved in AD.
The role of mTOR in age-related diseases
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Zofia Chrienova, Eugenie Nepovimova, Kamil Kuca
AD is an age-related metabolic neurodegenerative disorder whose exact cause and pathogenesis remain unclear. It is defined by a progressive cognitive decline and formation of senile plaques and neurofibrillary tangles. Several theories for the aetiology of the disease include the β-amyloid (Aβ) cascade hypothesis134–136 and tau hyperphosphorylation hypothesis137–139. However, effective therapies based on these two theories are still lacking. Indeed, growing evidence indicates that dysfunctional cerebral glucose metabolism is a pathophysiological feature in AD140–142. Glucose transportation (depending on the function of astrocytes and glucose transporters)143 and intracellular oxidative catabolism (including glycolysis, the pentose phosphate pathway in the cytoplasm, Krebs cycle, and oxidative phosphorylation) are two main processes involved in cerebral glucose metabolism. In patients with AD, glucose transportation abnormalities and intracellular metabolic alterations occur due to insulin resistance and mitochondrial dysfunction, respectively144,145.