Tau Phosphorylation in Female Neurodegeneration: Role of Estrogens, Progesterone, and Prolactin

Muñoz-Mayorga, Daniel; Guerra‐Araiza, Christian; Torner, Luz; Morales, Teresa

doi:10.3389/fendo.2018.00133

Cited by 37 publications

(21 citation statements)

References 81 publications

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“…Although several in vitro and in vivo studies in rodents suggest an impact of sex hormones (e.g. estrogens, progesterone and prolactin) and therefore gender on tau phosphorylation, there are so far no studies in AD patients validating these results in humans (for review see [ 33 ]). Future analyses of post mortem AD tissue and in vivo imaging of AD patients should shed light on the impact of gender on tau phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of different tau sites during progression of Alzheimer’s disease

Neddens

Temmel

Flunkert

et al. 2018

acta neuropathol commun

271

192

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Alzheimer’s disease is characterized by accumulation of amyloid plaques and tau aggregates in several cortical brain regions. Tau phosphorylation causes formation of neurofibrillary tangles and neuropil threads. Phosphorylation at tau Ser202/Thr205 is well characterized since labeling of this site is used to assign Braak stage based on occurrence of neurofibrillary tangles. Only little is known about the spatial and temporal phosphorylation profile of other phosphorylated tau (ptau) sites. Here, we investigate total tau and ptau at residues Tyr18, Ser199, Ser202/Thr205, Thr231, Ser262, Ser396, Ser422 as well as amyloid-β plaques in human brain tissue of AD patients and controls. Allo- and isocortical brain regions were evaluated applying rater-independent automated quantification based on digital image analysis. We found that the level of ptau at several residues, like Ser199, Ser202/Thr205, and Ser422 was similar in healthy controls and Braak stages I to IV but was increased in Braak stage V/VI throughout the entire isocortex and transentorhinal cortex. Quantification of ThioS-stained plaques showed a similar pattern. Only tau phosphorylation at Tyr18 and Thr231 was already significantly increased in the transentorhinal region at Braak stage III/IV and hence showed a progressive increase with increasing Braak stages. Additionally, the increase in phosphorylation relative to controls was highest at Tyr18, Thr231 and Ser199. By contrast, Ser396 tau and Ser262 tau showed only a weak phosphorylation in all analyzed brain regions and only minor progression. Our results suggest that the ptau burden in the isocortex is comparable between all analyzed ptau sites when using a quantitative approach while levels of ptau at Tyr18 or Thr231 in the transentorhinal region are different between all Braak stages. Hence these sites could be crucial in the pathogenesis of AD already at early stages and therefore represent putative novel therapeutic targets.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0557-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Phosphorylation of different tau sites during progression of Alzheimer’s disease

Neddens

Temmel

Flunkert

et al. 2018

acta neuropathol commun

271

192

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“…Deficiency of 17-β-estradiol (E2), a major form of estrogens, is implicated in age-related cognitive decline in human and non-human primates. Estrogens modulate hippocampal synaptic spine growth, structural plasticity, and neuronal excitability, which affect long-term potentiation in learning and memory ( Teyler et al, 1980 ; Brinton, 1993 ; Warren et al, 1995 ; Engler-Chiurazzi et al, 2016 ; Muñoz-Mayorga et al, 2018 ).…”

Section: Sex Steroid Hormones In Neuroprotectionmentioning

confidence: 99%

WWOX Phosphorylation, Signaling, and Role in Neurodegeneration

Liu

Lee

et al. 2018

Front. Neurosci.

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Homozygous null mutation of tumor suppressor WWOX/Wwox gene leads to severe neural diseases, metabolic disorders and early death in the newborns of humans, mice and rats. WWOX is frequently downregulated in the hippocampi of patients with Alzheimer’s disease (AD). In vitro analysis revealed that knockdown of WWOX protein in neuroblastoma cells results in aggregation of TRAPPC6AΔ, TIAF1, amyloid β, and Tau in a sequential manner. Indeed, TRAPPC6AΔ and TIAF1, but not tau and amyloid β, aggregates are present in the brains of healthy mid-aged individuals. It is reasonable to assume that very slow activation of a protein aggregation cascade starts sequentially with TRAPPC6AΔ and TIAF1 aggregation at mid-ages, then caspase activation and APP de-phosphorylation and degradation, and final accumulation of amyloid β and Tau aggregates in the brains at greater than 70 years old. WWOX binds Tau-hyperphosphorylating enzymes (e.g., GSK-3β) and blocks their functions, thereby supporting neuronal survival and differentiation. As a neuronal protective hormone, 17β-estradiol (E2) binds WWOX at an NSYK motif in the C-terminal SDR (short-chain alcohol dehydrogenase/reductase) domain. In this review, we discuss how WWOX and E2 block protein aggregation during neurodegeneration, and how a 31-amino-acid zinc finger-like Zfra peptide restores memory loss in mice.

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“…mRNA for PGRC2 has been previously identified within the hippocampus spanning Taenia tecta, Dentate gyrus and all CA regions indicating a widespread role within this brain region [30]. Progesterone exhibits properties of neuroprotection and a reduced progesterone level with aging has been linked with increased risk of AD development and altered tau expression and phosphorylation [31,32]. However, the relative influence of membrane bound progesterone receptors such as PGRC 1 and 2 (as opposed to canonical nuclear progesterone receptors) in the brain is presently unclear.…”

Section: Discussionmentioning

confidence: 99%

Identifying the beta-site amyloid precursor protein cleaving enzyme 1 interactome through the proximity-dependent biotin identification assay

Gabriel

Tinti

Fuller

et al. 2022

Neuroscience Letters

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Tau Phosphorylation in Female Neurodegeneration: Role of Estrogens, Progesterone, and Prolactin

Cited by 37 publications

References 81 publications

Phosphorylation of different tau sites during progression of Alzheimer’s disease

Phosphorylation of different tau sites during progression of Alzheimer’s disease

WWOX Phosphorylation, Signaling, and Role in Neurodegeneration

Identifying the beta-site amyloid precursor protein cleaving enzyme 1 interactome through the proximity-dependent biotin identification assay

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