Abnormal Tau phosphorylation of the Alzheimer‐type also occurs during mitosis

Abstract

In Alzheimer's disease, neurofibrillary degeneration results from the aggregation of abnormally phosphorylated Tau proteins into filaments and it may be related to the reactivation of mitotic mechanisms. In order to investigate the link between Tau phosphorylation and mitosis, Xenopus laevis oocytes in which most of the M-phase regulators have been discovered were used as a cell model. The human Tau isoform htau412 (2+3-10+) was microinjected into prophase I oocytes that were then stimulated by progesterone that activate cyclindependent kinase pathways. Hyperphosphorylation of the Tau isoform, which is characterized by a decrease of its electrophoretic mobility and its labelling by a number of phosphorylation-dependent antibodies, was observed at the time of germinal vesicle breakdown. Surprisingly, Tau immunoreactivity, considered as typical of Alzheimer's pathology (AT100 and phospho-Ser422), was observed in meiosis II. Because meiosis II is considered as a mitosis-like phase, we investigated if our observation was also relevant to a neuronelike model. Abnormal Tau phosphorylation was detected in mitotic human neuroblastoma SY5Y cells overexpressing Tau. Regarding AT100-immunoreactivity and phosphoSer422, we suggest that phosphatase 2A inhibition and a phosphorylation combination of mitotic kinases may lead to this Alzheimer-type phosphorylation. Our results not only demonstrate the involvement of mitotic kinases in Alzheimertype Tau phosphorylation but also indicate that Xenopus oocyte could be a useful model to identify the kinases involved in this process. Keywords: Alzheimer's disease, microtubule-associated Tau proteins, mitosis, oocyte maturation, phosphorylation. The mechanisms leading to neurodegenerative disorders referred to as tauopathies, such as Alzheimer's disease (AD) are still unknown but recent evidences had shown that neurones affected in these diseases and undergoing neurofibrillary degeneration may re-express some cell cycle genes notably implicated in the G 2 /M transition (Vincent et al. 1998;Husseman et al. 2000).Neurofibrillary degeneration is one of the neuropathological hallmarks of AD. It results from the aggregation of abnormally phosphorylated Tau proteins into paired helical filaments (PHFs). Tau proteins are mainly found in neurones. They play important roles in the polymerization and stability of microtubules (MTs). Moreover, phosphorylation is a key post-translational modification involved in their regulation. At least 30 phosphorylation sites have been described in Tau proteins, most of which occur on Ser/Pro and Thr/Pro motifs.Despite the fact that many phosphorylation sites are common between Tau aggregated into filaments in AD and normal Tau from biopsy-derived material, some differences exist and support the idea of an abnormal phosphorylation of Tau proteins in AD (for review see Buée et al. 2000). This latter is also a common feature among tauopathies. Despite the lack of evidence, a possible link may exist between abnormal Tau

p25/Cdk5-mediated retinoblastoma phosphorylation is an early event in neuronal cell death

“…Deleterious effect of p25-Cdk5 kinase in differentiated SY5Y cells p25-inducible cells were generated from SH-SY5Y cells, which constitutively overexpress Tau protein (Tau-SY5Y) (Delobel et al, 2002;Delobel et al, 2003). As previously shown, p25 protein was not found in mock Tau-SY5Y cells.…”

Spontaneous development of Alzheimer's disease‐associated brain pathology in a Shugoshin‐1 mouse cohesinopathy model

“…There is supporting evidence suggesting that mitotic cells are involved in amyloid‐β accumulation in human LOAD: (a) Human neurofibrillary tangles colocalized with MPM2 antigens, another mitotic marker (Kondratick & Vandré, 1996); (b) Abnormal Tau phosphorylation of the Alzheimer‐type also occurred during mitosis in human neuroblastoma SY5Y cells overexpressing Tau (Delobel et al., 2002); (c) APP Thr668 phosphorylation in mitosis correlated with increased processing of APP to generate Aβ and the C‐terminal fragment of APP (Judge, Hornbeck, Potter, & Padmanabhan, 2011); (d) Although p‐H3 localization is usually limited in chromatin in many other organs, human AD brain showed a cytoplasmic, diffused pattern of p‐H3 (Ogawa et al., 2003), which was recapitulated in the Sgo1 −/+ mouse brain (Figures 2d and 3a,b). These reports strongly suggest that human LOAD development can be aided by prolonged mitosis, which the Sgo1 −/+ model recapitulates.…”

Oxidative stress and its effect on cells functional activity of Alzheimer's disease

“…Его посттрансляционная модификация, обусловленная фосфорилированием, вовлекается в регуляцию этих процессов. Соответственно, процессы фосфорилирования регулируют связывающую функцию белка tau по отношению к тубулину [77].…”

“…В процессе развития АБ наблюдается скопление нейрофибриллярных сплетений, представленных в виде пучков парных спиральных филаментов, фосфорилированного и подвергшегося агрегации белка tau, связанного с микротрубочками нейронов [77][78][79]. В норме белок tau содержит 3 моля фосфатов на моль белка, а спаренное спиральное волокно белка tau (paired filament helical -PFH) -11 молей фосфата на моль белка.…”

“…В многочисленных исследованиях показано, что чрезмерная активация митотического выхода может быть связана с гиперфосфорилированием белка tau, что приводит к нарушению аксонального транспортного механизма, потере клеточной формы, дегенерации аффективных нейронов и прогрессированию АБ [77,78,83,85]. Гиперфосфорилирование белков обусловлено нарушением соотношения киназной и фосфатазной активностей.…”