Estradiol Attenuates Tau Hyperphosphorylation Induced by Upregulation of Protein Kinase-A

The populations with olfactory dysfunction show an increased chance for hippocampus-dependent episodic memory deficit. Although it is known that the olfactory information projects to the hippocampus through entorhinal cortex layer II, the molecular mechanisms linking olfactory deficit to the hippocampus is not understood. Using bilateral olfactory bulbectomy (OBX) as a model, we found that OBX induced memory deficits with activation of several memory-related protein kinases in the hippocampal extracts, including glycogen synthase kinase-3β (GSK-3β), protein kinase A (PKA), extracellular-signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), phosphatidylinositol-3-kinase (PI3K), and protein kinase B (PKB). The OBX rats also show suppression of long-term potentiation (LTP); reduction of synapsin I, synaptophysin, NR2A/B, and PSD95; thinner presynaptic active zone and postsynaptic density with enlarged synaptic space; decreased spine numbers and mushroom-type spines; and tau hyperphosphorylation. After injection of SB216763 for several weeks by vena caudalis, selective inhibition of GSK-3β ameliorated the OBX-induced memory deficits with recovery of the synaptic components and tau phosphorylation. Furthermore, genetic ablation of GSK-3β by lentivirus-packed shRNA effectively rescued the memory deficits, synaptic disorder, and tauopathy. Our data indicate that GSK-3 activation mediates the olfactory deficits to the hippocampus, and targeting GSK-3 blocks the pathological connection.

show abstract

“…The Western blotting was carried as described previously [48,49]. The rats were sacrificed at 24 h after the step-through test.…”

Section: Western Blottingmentioning

confidence: 99%

Activation of Glycogen Synthase Kinase-3 Mediates the Olfactory Deficit-Induced Hippocampal Impairments

Huang

Wang

et al. 2014

Mol Neurobiol

Self Cite

View full text Add to dashboard Cite

show abstract

“…Specifically, E 2 and P4 regulate tau phosphorylation through the glycogen synthase kinase-3 (GSK-3 ) pathway [57,58]. Estrogen can reduce GSK-3 activity [58] and lower tau hyperphosphorylation through the wnt signaling pathway and dickkopf-1 [59] as well as through the protein kinase A pathway [60]. Progesterone can decrease expression of both tau and GSK-3 [61].…”

Section: Estrogen Regulation Of Tau Hyperphosphorylationmentioning

confidence: 99%

The Potential Use of Hormone-Based Therapeutics for the Treatment of Alzheimers Disease

Carroll¹,

Rosario²

2012

CAR

View full text Add to dashboard Cite

In both men and women, age-related loss of sex steroid hormones has been linked to an increased risk for Alzheimer's disease (AD). The primary female hormone estrogen, and the primary male hormone testosterone have numerous protective effects in the brain relevant to the prevention of AD such as the promotion of neuron viability, reduction of β- amyloid accumulation and alleviation of tau hyperphosphorylation. Therefore it has been hypothesized that the precipitous loss of these hormones either through menopause or normal aging, can increase susceptibility to AD pathogenesis. This review will discuss the basic science research and epidemiological evidence largely supporting this hypothesis, as well as the estrogen-based hormone therapy clinical findings that have recently shed doubt on this theory. The complications associated with estrogen-based hormone therapy such as the inclusion of a progestogen, hormone responsiveness with age, and natural vs. synthetic hormones will be discussed. Further, we will outline the cancer risks facing both estrogen and testosterone-based hormone therapy. Most importantly, this review will discuss the present and future strategies to translate the neuroprotective properties of sex steroid hormones into safe and efficacious treatments for AD. One of the most promising translational tools thus far may be the development of selective estrogen and androgen receptor modulators. However, additional research is needed to optimize these and other translational tools towards the successful use of hormone therapies in both men and women to delay, prevent, and or treat AD.

show abstract

“…This results from the high number (about 42) of Ser/Thr residues available in tau [44], which make this protein a good target for several kinases [45], such as cyclindependent kinase 5 (Cdk5) [46,47], glycogen synthase kinase 3 beta (Gsk3 ) [48,49] or protein kinase A (PKA) [50,51]. Upon hyperphosphorylation, tau no longer associates with the microtubules and can aggregate in the form of filaments and tangles [52,53].…”

Section: Hyperphosphorylation Of Taumentioning

confidence: 99%

Cell Cycle Re-Entry in Alzheimers Disease: A Major Neuropathological Characteristic?

Lopes¹,

Oliveira²,

Agostinho

2009

CAR

View full text Add to dashboard Cite

Alzheimer's disease (AD) is an irreversible, progressive brain disease that slowly destroys memory and thinking skills. With over 26 million patients in 2006, AD is the most prevalent neurodegenerative disease worldwide. Different hypotheses have been suggested to explain the pathogenesis of AD, like those involving inflammation, mitochondrial dysfunction or oxidative stress. Many of these studies have addressed amyloid plaque formation, tau hyperphosphorylation and apoptotic neuronal loss, the three main histopathological hallmarks of this disease. Increasing evidences, however, suggest another feature that can also be considered a neuropathological marker for AD: ectopic cell cycle re-entry. Cell cycle events have been frequently registered in the brains of AD patients. Although the exact starting point of cell cycle re-entry remains unclear, a number of subsequent cascades, which include events such as kinase upregulation, DNA replication and cytoskeletal alterations, have already been described. There are also increasing reports suggesting that cell cycle reactivation in mature neurons occurs as part of the apoptotic process. Upon a brief overview of the different theories and models addressing cell cycle reactivation in AD, we will describe possible mechanisms that trigger cell cycle re-entry, with special attention to links between this feature and the main neuropathological markers of AD. Finally, we will also analyze possible similarities between cell cycle dysregulation in AD and in other pathologies, such as Prion-Related Encephalopathies.

show abstract

Estradiol Attenuates Tau Hyperphosphorylation Induced by Upregulation of Protein Kinase-A

Cited by 51 publications

References 55 publications

Activation of Glycogen Synthase Kinase-3 Mediates the Olfactory Deficit-Induced Hippocampal Impairments

Activation of Glycogen Synthase Kinase-3 Mediates the Olfactory Deficit-Induced Hippocampal Impairments

The Potential Use of Hormone-Based Therapeutics for the Treatment of Alzheimers Disease

Cell Cycle Re-Entry in Alzheimers Disease: A Major Neuropathological Characteristic?

Contact Info

Product

Resources

About