The Molecular Mechanism of Chronic High-Dose Corticosterone-Induced Aggravation of Cognitive Impairment in APP/PS1 Transgenic Mice.

Clinical studies have found that some Alzheimer's disease (AD) patients suffer from Cushing's syndrome (CS). CS is caused by the long-term release of excess glucocorticoids (GCs) from the adrenal gland, which in turn, impair brain function and induce dementia. Thus, we investigated the mechanism of the effect of corticosterone (CORT) on the development and progression of AD in a preclinical model. Specifically, the plasma CORT levels of 9-month-old APP/PS1 Tg mice were abnormally increased, suggesting an association between GCs and AD. Long-term administration of CORT accelerated cognitive dysfunction by increasing the production and deposition of ß-amyloid (Aß). The mechanism of action of CORT treatment involved stimulation of the expression of BACE-1 and presenilin (PS) 1 in in vitro and in vivo. This observation was confirmed in mice with adrenalectomy (ADX), which had lower levels of GCs. Moreover, the glucocorticoid receptor (GR) mediated the effects of CORT on the stimulation of the expression of BACE-1 and PS1 via the PKA and CREB pathways in neuroblastoma N2a cells. In addition to these mechanisms, CORT can induce a cognitive decline in APP/PS1 Tg mice by inducing apoptosis and decreasing the differentiation of neurons.

Cyclooxygenase-2 Induced the ß-Amyloid Protein Deposition and Neuronal Apoptosis Via Upregulating the Synthesis of Prostaglandin E2 and 15-Deoxy-Δ12,14-prostaglandin J2.

Elevated levels of cyclooxygenase-2 (COX-2) and prostaglandins (PGs) have been shown to be involved in the pathogenesis of Alzheimer's disease. Analysis of the underlying mechanisms elucidated a function of sequential PGE2 and PGD2 synthesis in regulating ß-amyloid protein (Aß) deposition by modulating tumor necrosis factor α (TNF-α)-dependent presenilin (PS)1/2 activity in COX-2 and APP/PS1 crossed mice. Specifically, COX-2 overexpression accelerates the expression of microsomal PGE synthase-1 (mPGES-1) and lipocalin-type prostaglandin D synthase (L-PGDS), leading to the synthesis of PGE2 and 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) in 6-month-old APP/PS1 mice. Consequently, PGE2 has the ability to increase Aß production by enhancing the expression of PS1/2 in a TNF-α-dependent manner, which accelerates the cognitive decline of COX-2/APP/PS1 mice. More interestingly, low concentrations of 15d-PGJ2 treatment facilitate the effects of PGE2 on the deposition of Aß via TNF-α-dependent PS1/2 mechanisms. In contrast, high concentrations of 15d-PGJ2 treatment inhibit the deposition of Aß via suppressing the expression of TNF-α-dependent PS1/2. In this regard, a high concentration of 15d-PGJ2 appears to be a therapeutic agent against Alzheimer's disease. However, the high 15d-PGJ2 concentration treatment induces neuronal apoptosis via increasing the protein levels of Bax, cleaved caspase-3, and DFF45, which further impairs the learning ability of APP/PS1 mice.

Calcium Ions Stimulate the Hyperphosphorylation of Tau by Activating Microsomal Prostaglandin E Synthase 1.

Alzheimer's disease (AD) is reportedly associated with the accumulation of calcium ions (Ca2+), and this accumulation is responsible for the phosphorylation of tau. Although several lines of evidence demonstrate the above phenomenon, the inherent mechanisms remain unknown. Using APP/PS1 Tg mice and neuroblastoma (N)2a cells as in vivo and in vitro experimental models, we observed that Ca2+ stimulated the phosphorylation of tau by activating microsomal PGE synthase 1 (mPGES1) in a prostaglandin (PG) E2-dependent EP receptor-activating manner. Specifically, the highly accumulated Ca2+ stimulated the expression of mPGES1 and the synthesis of PGE2. Treatment with the inhibitor of Ca2+ transporter, NMDAR, attenuated the expression of mPGES1 and the production of PGE2 were attenuated in S(+)-ketamine-treated APP/PS1 Tg mice. Elevated levels of PGE2 were responsible for the hyperphosphorylation of tau in an EP-1-, EP-2-, and EP-3-dependent but not EP4-dependent cyclin-dependent kinase (Cdk) 5-activating manner. Reciprocally, the knockdown of the expression of mPGES1 ameliorated the expected cognitive decline by inhibiting the phosphorylation of tau in APP/PS1 Tg mice. Moreover, CDK5 was found to be located downstream of EP1-3 to regulate the phosphorylation of tau though the cleavage of p35 to p25. Finally, the phosphorylation of tau by Ca2+ contributed to the cognitive decline of APP/PS1 Tg mice.

Cyclooxygenase-2 is Essential for Mediating the Effects of Calcium Ions on Stimulating Phosphorylation of Tau at the Sites of Ser 396 and Ser 404.

Alzheimer's disease (AD) is reported to be associated with the accumulation of calcium ions (Ca2+), which is responsible for the phosphorylation of tau. Although a series of evidence have demonstrated this phenomenon, the inherent mechanisms remain unknown. Using tauP301S and cyclooxygenase-2 (COX-2) transgenic mice and neuroblastoma (n)2a cells as in vivo and in vitro experimental models, we found that Ca2+ stimulates the phosphorylation of tau by activating COX-2 in a prostaglandin (PG) E2-dependent EP receptor-activating manner. Specifically, Ca2+ incubation stimulated COX-2 and PGE2 synthase activity, microsomal PGE synthase 1 and the synthesis of PGE2 by activating the transcriptional activity of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in n2a cells. Elevated levels of PGE2 were responsible for phosphorylating tau in an EP-1, -2, and -3 but not EP4-dependent glycogen synthase kinase 3-activating manner. These observations were corroborated by results that showed tau was phosphorylated when it colocalized with activated COX-2 in tauP301S and COX-2 transgenic mice or n2a cells. To further validate these observations, treatment of mice with the COX-2 inhibitor rofecoxib decreased the phosphorylation of tau via EP1-3 but not EP4. Collectively, our observations fill the gaps between Ca2+ and the phosphorylation of tau in a COX-2-dependent mechanism, which potentially provides therapeutic targets for combating AD.

Magnesium Ions Inhibit the Expression of Tumor Necrosis Factor α and the Activity of γ-Secretase in a ß-Amyloid Protein-Dependent Mechanism in APP/PS1 Transgenic Mice.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive impairment. The neuropathological features of AD are the aggregation of extracellular amyloid ß-protein (Aß) and tau phosphorylation. Recently, AD was found to be associated with magnesium ion (Mg2+) deficit and tumor necrosis factor-alpha (TNF-α) elevation in the serum or brains of AD patients. To study the relationship between Mg2+ and TNF-α, we used human- or mouse-derived glial and neuronal cell lines or APP/PS1 transgenic (Tg) mice as in vitro and in vivo experimental models, respectively. Our data demonstrates that magnesium-L-threonate (MgT) can decrease the expression of TNF-α by restoring the levels of Mg2+ in glial cells. In addition, PI3-K/AKT and NF-κB signals play critical roles in mediating the effects of Mg2+ on suppressing the expression of TNF-α. In neurons, Mg2+ elevation showed similar suppressive effects on the expression of presenilin enhancer 2 (PEN2) and nicastrin (NCT) through a PI3-K/AKT and NF-κB-dependent mechanism. As the major components of γ-secretase, overexpression of presenilin 1 (PS1), PEN2 and NCT potentially promote the synthesis of Aß, which in turn activates TNF-α in glial cells. Reciprocally, TNF-α stimulates the expression of PEN2 and NCT in neurons. The crosstalk between TNF-α and Aß in glial cells and neurons could ultimately aggravate the development and progression of AD.