O-linked β-N-acetylglucosaminidase inhibitor attenuates β-amyloid plaque and rescues memory impairment.

Deposition of β-amyloid (Aβ) as senile plaques and disrupted glucose metabolism are two main characteristics of Alzheimer's disease (AD). It is unknown, however, how these two processes are related in AD. Here we examined the relationship between O-GlcNAcylation, which is a glucose level-dependent post-translational modification that adds O-linked β-N-acetylglucosamine (O-GlcNAc) to proteins, and Aβ production in a mouse model of AD carrying 5XFAD genes.

The failure of mitochondria leads to neurodegeneration: Do mitochondria need a jump start?

Mitochondria are the power engine generating biochemical energy in the cell. Mitochondrial dysfunction and bioenergy deficiency is closely linked to the pathogenesis of neurodegenerative disorders. Mitochondria play a variety of roles by integrating extracellular signals and executing important intracellular events in neuronal survival and death.

Rac1 changes the substrate specificity of gamma-secretase between amyloid precursor protein and Notch1.

Beta amyloid peptide is generated from amyloid precursor protein (APP) by proteolytic cleavage of beta- and gamma-secretases, and plays a critical role in the pathogenesis of Alzheimer's disease. Since gamma-secretase cleaves several proteins including APP and Notch in a number of cell types, it is important to understand the conditions determining gamma-secretase substrate specificity. In the present study, inhibition of Rac1 attenuated gamma-secretase activity for APP, resulting in decreased production of the APP intracellular domain but accumulated C-terminal fragments (APP-CTF).

Effect of ischemic neuronal insults on amyloid precursor protein processing.

The nature of the association between ischemic stroke and Alzheimer's disease (AD) at the cellular and molecular level is still unknown. We evaluated the effect of ischemic neuronal insults on the regulation of amyloid precursor protein (APP) processing. We used an in vitro model of cerebral ischemia (oxygen-glucose deprivation) to evaluate the effect of ischemic neuronal insults on the amyloidogenic and non-amyloidogenic pathways using human neuroblastoma cell line and primary cultured cells of transgenic mice which expressed human APP (Tg2576).

Profiling proteins related to amyloid deposited brain of Tg2576 mice.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder that is characterized by the extracellular deposition of beta-amyloid and intracellular hyperphosphorylation of tau in the cortex and hippocampus of the brain. These characterizations are caused by abnormal expression, modification and deposition of certain proteins. Post-translational modifications of proteins including oxidation and nitration might be involved in the pathogenesis of AD.

Amyloid beta peptide directly inhibits PKC activation.

A putative protein kinase C (PKC) pseudosubstrate domain in beta amyloid (Abeta) suggests a potential interaction between Abeta and PKC. In this study, we investigated whether and how Abeta interacts with PKC. Abeta peptides inhibited PKC phosphorylation in a dose-dependent manner in cell-free in vitro condition, suggesting a direct interaction between Abeta and PKC.

Neuroprotective effect of genistein against beta amyloid-induced neurotoxicity.

Estrogen is beneficial to patients with Alzheimer's disease (AD) but has a limited clinical use due to its proliferative and oncogenic effects on non-neuronal cells responsive to estrogen. In an attempt to find an estrogen substitute that retains the beneficial effects of estrogen with minimal side effects, we compared the neuroprotective and proliferative effects of genistein, a selective estrogen receptor (ER) beta-agonist, with those of estrogen. Genistein and 17beta-estradiol showed comparable levels of protection against Abeta-induced deaths of cultured SH-SY5Y human neuroblastoma cells, which were blocked by an estrogen receptor antagonist, ICI 182,780.

Lovastatin enhances Abeta production and senile plaque deposition in female Tg2576 mice.

A recent clinical study showed that statins, which are inhibitors of cholesterol biosynthesis pathway, reduced the prevalence of Alzheimer's disease (AD). Animal studies that have employed high cholesterol diet indicate significant relationship between cholesterol level and senile plaque deposition. Here, we investigated the effects of lovastatin on beta-amyloid production and senile plaque deposition in an animal model of AD (Tg2576 mice).