Beta amyloid and Tau proteins (HUMAN transglutaminase substrates, AS GLUTEN and CASEIN) LECMA скачать в хорошем качестве

Beta amyloid and Tau proteins (HUMAN transglutaminase substrates, AS GLUTEN and CASEIN) LECMA

FOTGCREN HYPOTHESIS: A tale of bugs and foods: Hwp1 versus gluten and casein (v3)    • A tale of bugs and foods: Hwp1 versus glut...   WANG 2008: http://www.ncbi.nlm.nih.gov/pmc/artic... Alzheimer's disease (AD) affects millions of people worldwide with, unfortunately, ever increasing incidence. Currently there is no cure for this devastating disease, and even symptomatic relief remains modestly effective. Underlying the behavioral and cognitive decline of AD is the progressive neuronal dysfunction and ultimately cell death by processes that are not fully understood. Grossly, the brain of AD usually shows atrophy with reduced volume and weight due to extensive loss of neurons in the neocortex. The most characteristic pathological structures of AD pathology are senile plaques and neurofibrillary tangles (NFTs): Histologically, the most remarkable and consistent morphological features are the neuritic senile plaques and neurofibrillary tangles (NFTs). SENILE PLAQUES: The major proteinaceous component of the plaques is the extensively cross-linked β-amyloid (Aβ) with non-amyloid components comprising the core of the plaques. The major components in senile plaques are (β-amyloid (Aβ)) Aβ1-40 and Aβ1-42. Some senile plaques have a condensed core that contains truncated α-synuclein fragments. Small amounts of neurofilaments can also be found in plaques. NEUROFIBRILLARY TANGLES: Mature NFTs are composed of aggregates of hyperphosphorylated tau and many other proteins, such as ubiquitin and neurofilaments. The dominant component of NFTs is the hyperphosphorylated tau, a microtubule binding protein. Recently, α-synuclein had also been found in NFTs. TRANSGLUTAMINASE: The mechanism underlying the extensive protein cross-linking in AD is still unknown, but tissue transglutaminase (tTG) has been implicated in this process. Iso-peptides (the catalytic product of tTG) have been found in plaques and tangles. tTG and tTG activity are elevated in AD brains compared to controls. Tissue TG Catalyzes the Cross-Linking of Critical Proteins of AD Pathology. So far, all of those major components found in senile plaques and NFTs have been shown to be substrates of tTG. The level of isopeptide bonds, the catalytic product of tTG, was increased in AD brains compared to controls. The results suggest that accumulation of cross-linked protein gradually results in neuronal dysfunction and cognitive decline. The first suggestion that tTG may play a role in AD was made by Selkoe and colleagues when they showed tTG can covalently cross-link neurofilament proteins into insoluble polymers in vitro by forming γ-glutamyl-ε-lysine intermolecular bridges. Later studies indicated that tTG can catalyze cross-linking of Aβ, amyloid precursor protein (APP), tau and α-synuclein in addition to neurofilament proteins. Tissue TG Cross-Links Aβ: Using the incorporation of site-specific probes followed by enzymatic digestion and sequencing of tracer-containing fractions, Lys16, Lys28 and Gln15 in Aβ were all susceptible to cross-linking by tTG. Immunochemical demonstration of tTG in amyloid plaques in AD brains suggests a role in plaque formation by cross-linking Aβ or other components. The in vivo data demonstrating a direct link between tTG and cross-linking of Aβ are still missing. Tissue TG Cross-Links tau Tau protein is an excellent substrate of TG and tTG both in vitro and in vivo. Dudek and colleagues showed that in the presence of TG tau formed macromolecular complexes. Cross-linking site analysis of human tau (tau23 and tau40) showed that eight glutamines can function as amine acceptor residues, with two major sites at Gln351 and Gln424. In addition, 10 lysine residues were identified as amine donors, most of which are clustered adjacent to the microtubule binding repeats of tau in regions known to be solvent accessible in filamentous tau. Studies on human specimens indicate that tTG may be involved in cross-linking of tau pathology seen in AD brains. Isopeptides and tau protein co-localized in neurofibrillary tangles Summary: Extensive protein cross-linking and aggregation involving a variety of proteins are commonly occurring molecular processes during the pathogenesis of AD. The initiating factors are likely to be environmental insults (e.g., trauma, inflammation or ischemic damage) that lead to increased tTG activity and increased cross-linking for tau, Aβ and other molecules, which leads to functional impairment, structural lesions characteristic of AD (e.g., plaques and tangles) and eventually neuronal death. If the relationship between increased tTG and deleterious cross-linking of proteins such as α-synuclein, tau and Aβ are critical to AD pathogenesis, therapeutic measures should be developed to manipulate tTG protein and activity levels. SOURCE: Original video: Mechanisms and secrets of Alzheimer's disease: exploring the brain Fondation Vaincre Alzheimer    • Mechanisms and secrets of Alzheimer's dise...