Pathophysiology of Alzheimer’s disease
Howard H. Feldman in Atlas of Alzheimer's Disease, 2007
One of the main functions of normal tau protein within neurons is to bind microtubules, promoting normal axonal transport. This binding of tau to microtubules is considered necessary to maintain the axonal integrity of neurons. There are six isoforms of tau protein in the human brain. The phosphorylation state of these tau isoforms determines their binding affinity to microtubules. In AD, tau becomes pathologically hyperphosphorylated. This triggers a cascade of events that includes tau detaching from microtubules and misfolding/aggregating into phosphorylated tau. This destabilizes microtubules, disrupts axonal transport, and leads to neuronal death.5 NFTs are the end result of the aggregation of hyperphosphorylated tau (see Figure 4.3).6
Pharmacological Management of Alzheimer’s Disease
Sahab Uddin, Rashid Mamunur in Advances in Neuropharmacology, 2020
The only definite risk factors for the sporadic are the E4 allele of apolipoprotein E and senescence. The plaques are constituted chiefly of the neurotoxic peptide. The Aβ is the by-product of the cleavage of a large precursor protein (APP) by enzymes (β-secretase and γ-secretase) (Allen et al., 2011). However, the Aβ is invisible in case of APP, which is cleaved by the enzyme α-secretase. NFTs mainly comprise of the tau protein that is a microtubule-associated protein. The function of tau protein is to facilitate the neuronal transport system by binding with microtubules in cells. In case of the AD, tau is uncoupled microtubules and aggregates into tangles by inhibiting transport and resulting in microtubule disassembly. It also depends on the phosphorylation of tau(Allen et al., 2011; Ravi et al., 2018). In a hypothesis, it has been reported that the mitochondrial dysfunction leads to amyloidosis, alter the kinase and tau phosphatase enzyme, and cell cycle re-entry (Moreira, 2018; Shoshan-Barmatz et al., 2018).
Special considerations: Alzheimer’s disease
Hemanshu Prabhakar, Charu Mahajan, Indu Kapoor in Essentials of Geriatric Neuroanesthesia, 2019
Beta-amyloid is produced following cleavage of the transmembrane protein amyloid precursor protein (APP) by beta-secretase and gamma-secretase (14). It is unclear exactly what role APP or beta-amyloid play in a normally functioning neuron, but an imbalance between the production and clearance of beta-amyloid can lead to pathologic accumulation that may play a causative role in AD (15). Tau protein is an important microtubule-associated protein that helps to stabilize the neuron's cytoskeleton by binding to microtubules (13). In vitro studies suggest that in normal cellular function the activity of tau protein is regulated by phosphorylation. When tau is phosphorylated, there is a reduction in the binding of tau to microtubules which could be an important step for the regulation of neurite outgrowth and axonal transport in the neuron. In AD, as well as all other known diseases involving dysregulated tau, there is rampant phosphorylation of tau proteins resulting in cytoskeletal abnormalities and accumulation of hyperphosphorylated tau. While neurofibrillary tangles formed from hyperphosphorylated tau can generate over decades independent of plaques or the presence of AD (16), both beta-amyloid and hyperphosphorylated tau are necessary for AD pathology.
Polyamine biomarkers as indicators of human disease
Published in Biomarkers, 2021
Mohsin Amin, Shiying Tang, Liliana Shalamanova, Rebecca L. Taylor, Stephen Wylie, Badr M. Abdullah, Kathryn A. Whitehead
In current practice, the presence of AD is confirmed through measurements of amyloid-beta protein, tau protein and phospho-tau levels in the patient’s cerebrospinal fluid (Figure 6) (Galimberti and Scarpini 2010, Sharma and Singh 2016). Neurofibrillary tangles are a fundamental pathological hallmark of AD and are aggregates of hyperphosphorylated tau protein (Serrano-Pozo et al.2011). Tau protein is a microtubule-binding protein that is mainly expressed in neurons (Stoothoff and Johnson 2005). The hyperphosphorylation of this protein is what is thought to be one of the causes of tau dysfunction, causing binding to the microtubules in the neurons, leading to the eventual disruption of the neuronal microtubules with subsequent impairment of axoplasmic flow and loss of neuronal connectivity (Grundke-Iqbal et al.1986, Iqbal et al.2000, Blennow and Zetterberg 2018). Studies have suggested that the pathological severity of AD is at its greatest during the early stages of the disease. Due to the invasive nature of current diagnosis and treatment strategies, research aims are focusing towards alternate biomarker sources thus, aiming at slowing the progression of neurodegeneration (Thalhauser and Komarova 2012, Nelson and Tabet 2015, Folch et al.2016).
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).
A review of potential neuropathological changes associated with ketamine
Published in Expert Opinion on Drug Safety, 2022
Danica Nogo, Hana Nazal, Yuetong Song, Kayla M. Teopiz, Roger Ho, Roger S. McIntyre, Leanna M.W. Lui, Joshua D. Rosenblat
Tau proteins, a type of microtubule-associated protein that regulates the organization of neuronal microtubules within the central nervous system [34,35], act as a transport channel of axons and dendrites during neural maturation [36]. The amino-terminal region of the protein has previously been found to be essential in the determination of axonal diameter; and the carboxy-terminal region controls microtubule-binding ability, as well as microtubule stabilization and polymerization [35]. The aggregation of the foregoing tau proteins into neurofibrillary tangles has been correlated to the onset of several neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease, and progressive supranuclear palsy [34,37]. The foregoing neurodegenerative diseases are often referred to as ‘tauopathies,’ and are all characterized by an intracellular accumulation of tau [35,37].
Related Knowledge Centers
- Alternative Splicing
- Axon
- Central Nervous System
- Cerebral Cortex
- Microtubule
- Protein Isoform
- Astrocyte
- Gene
- Microtubule-Associated Protein
- Neuron