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Dementia
Published in Henry J. Woodford, Essential Geriatrics, 2022
FTD has several variants, including Pick disease. This latter condition is distinguished pathologically by the presence of Pick bodies, which are argentophilic intracellular inclusions. Tau protein is a normal cellular component of microtubules. FTD is associated with abnormal processing of this protein, often with hyperphosphorylation. Other conditions associated with tau abnormalities include PSP and corticobasal degeneration (CBD) (see page 188 and page 189) – together termed ‘tauopathies'. As suggested by the name, FTD predominantly affects the frontal and anterior temporal lobes. It is a more common cause of younger-onset dementia and uncommonly presents after age 65.50
Role of Vitamin D and Antioxidant Functional Foods in the Prevention and Treatment of Alzheimer’s Disease Pathology
Published in Abhai Kumar, Debasis Bagchi, Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
Secondary accumulation of tau protein has also been considered a determinant factor in AD progression. Beta-amyloid induces increased tau phosphorylation and translocation to the cytoplasm, which are associated with neurodegeneration. Cerebrospinal fluid (CSF) phosphorylated tau (P-tau) and cortical tau are considered disease biomarkers (Jack et al., 2018). The primary biological function of tau may be directly associated with microtubule stabilization (Kneynsberg, Combs, Christensen, Morfini, & Kanaan, 2017). Tau binds microtubules and hyperphosphorylation causes aberrant aggregation to the cytoskeletal proteins, which, in turn, cause axonal transport malfunction (Sanabria-Castro et al., 2017). Hyperphosphorylation also causes a change in the conformation of tau leading to the disassembly of the microtubule and formation of paired helical filaments, which then cause aggregation and formation of NFT. Once affected, tau spreads through the brain, via transcellular spreading, and can induce synaptotoxicity (Demaegd, Schymkowitz, & Rousseau, 2018). Axonal pathology is a common outcome of many human tauopathies. In AD, axonal demyelination/dystrophy can occur in the prodromal disease stage that progresses from the cortex into the corpus callosum and has a direct correlation with cognitive decline (Kneynsberg et al., 2017).
Issues in aging following traumatic brain injury
Published in Mark J. Ashley, David A. Hovda, Traumatic Brain Injury, 2017
Grace S. Griesbach, Mark J. Ashley, Alan Weintraub
In addition to amyloid plaques, the appearance of neurofibrilliary tangles (NFT) is considered one of the classical histopathology markers for AD.170 NFTs consist of aggregations of tau protein within neurons. Tau protein’s main function is to stabilize microtubules. However, when hyperphosphorylated, it leads to the formation of tangles. Tauopathies are also observed in other forms of dementia. Within the context of TBI, tauopathies are predominantly observed following cumulative TBIs. The presence of NFTs has been identified in the brains of boxers who suffered from a form of dementia that was initially identified as being “punch drunk” or having dementia pugilistica. It has recently been recognized as CTE.171,172
Emerging Symptomatic Treatment of Chronic Traumatic Encephalopathy (CTE): a narrative review
Published in Expert Opinion on Pharmacotherapy, 2023
Carlo Rossi, Nicole Campese, Carlo Colosimo
To increase physicians’ and patients’ awareness of CTE, promote TES symptoms early recognition, as well as a better understanding of CTE pathophysiological pathways, and the identification of clinical, fluid, and neuroimaging biomarkers, are crucial unmet needs to be addressed in future trials with potential disease-modifying compounds. Pre-clinical studies were designed to investigate the treatment of tauopathies by targeting known molecular pathways. Anti-p-tau immunotherapy could reduce p-tau spreading and disease progression. Other proposed therapeutic targets include tau acetylation, tau phosphorylation, and modulation of neuroinflammation but only a few pre-clinical studies have explored these experimental treatments in rodent models specific for CTE, likely due to their recent introduction [47].
Clinical development of passive tau-based immunotherapeutics for treating primary and secondary tauopathies
Published in Expert Opinion on Investigational Drugs, 2023
Francesco Panza, Vittorio Dibello, Rodolfo Sardone, Fabio Castellana, Roberta Zupo, Luisa Lampignano, Ilaria Bortone, Roberta Stallone, Nicoletta Cirillo, Christian Damiani, Mario Altamura, Antonello Bellomo, Antonio Daniele, Vincenzo Solfrizzi, Madia Lozupone
From a neuropathological point of view, tauopathies are characterized by insoluble aggregates of hyperphosphorylated tau protein, but the clinical spectrum of these conditions is various, complex and with partly overlapping presentations [5]. Currently, we recognize more than 26 different tauopathies [6], classified as primary and secondary/nonprimary tauopathies [7,8]. Primary tauopathies considered to be diseases are characterized by increased and abnormal tau aggregates as the primary underlying neurodegenerative process. However, some primary tauopathies may not have an accompanying clinical syndrome and could be considered age-related entities. Secondary/nonprimary tauopathies are characterized by a deposition of also another protein together with tau pathology. However, in secondary tauopathies, the role of tau pathology may not necessarily be downstream to this other protein-associated pathology [4], so recommending to use the term mixed tauopathies. The best known and studied secondary/mixed tauopathy is Alzheimer’s disease (AD) with amyloid-β (Aβ) depositions also present as a neuropathological hallmark in addition to abnormal tau deposition primarily manifesting as neurofibrillary tangles (NFT). Chronic traumatic encephalopathy (CTE) [9], subacute sclerosing panencephalitis [10], myotonic dystrophy [10], Lewy body disorders, Down’s syndrome [11], and Niemann-Pick disease-type C [11] are other secondary/mixed tauopathies.
PTK2 regulates tau-induced neurotoxicity via phosphorylation of p62 at Ser403
Published in Journal of Neurogenetics, 2023
Shinrye Lee, Myungjin Jo, Younghwi Kwon, Yu-Mi Jeon, Seyeon Kim, Kea Joo Lee, Hyung-Jun Kim
Microtubule-associated protein tau (MAPT/Tau) is a neuronal protein that mediates axonal transport of cellular components along microtubules by binding to microtubules and regulating their assembly and stabilization (Cuchillo-Ibanez et al.,2008; Gustke, Trinczek, Biernat, Mandelkow, & Mandelkow, 1994). Tauopathies are one of the most common proteinopathies associated with neurodegenerative diseases, including Alzheimer’s disease (AD) and frontotemporal dementia (FTD). The presence of paired helical filaments (PHFs) and neurofibrillary tangles (NFTs) inside neurons or glial cells is the pathological hallmark of AD. In addition, FTD with parkinsonism linked to chromosome-17 (FTDP-17) is characterized by filamentous inclusions that are composed of hyperphosphorylated Tau (Ballatore, Lee, & Trojanowski, 2007; Lee, Goedert, & Trojanowski, 2001; Williams, 2006). Under pathological conditions, Tau undergoes various posttranslational modifications and detaches from microtubules to form insoluble aggregates (Gendron & Petrucelli, 2009; Iqbal, Liu, & Gong, 2016; Krüger & Mandelkow, 2016).