Elevated Β-amyloid Research Articles

β-Asarone Mitigates Amyloidosis and Downregulates RAGE in a Transgenic Mouse Model of Alzheimer's Disease.

Elevated β-amyloid (Aβ) is a hallmark of Alzheimer's disease (AD). Recent evidence has suggested that the receptor of advanced glycation end products (RAGE) is a key target for Aβ-induced perturbation in AD, and blockade of RAGE significantly alleviates synaptic injury. Our previous study has suggested that β-asarone could reduce neuronal apoptosis and improve memory deficits in β-amyloid precursor protein and presenilin-1 (APP/PS1) double transgenic AD-model mice. In the present study, we evaluated the effects of β-asarone on amyloidosis in APP/PS1 mice. We found that the survival of neurons of APP/PS1 mice was improved by β-asarone, meanwhile, β-asarone decreased Aβ deposition and down-regulated Aβ1-42 levels in cortex and hippocampus of APP/PS1 mice brain. Interestingly, the level of RAGE was also significantly down-regulated by β-asarone. Our findings suggest that β-asarone might be effective for the treatment of AD, and the decreasing effects of β-asarone on Aβ might associate with its down-regulation of RAGE.

Paradoxical Condensation of Copper with Elevated β-Amyloid in Lipid Rafts under Cellular Copper Deficiency Conditions: IMPLICATIONS FOR ALZHEIMER DISEASE

Redox-active copper is implicated in the pathogenesis of Alzheimer disease (AD), beta-amyloid peptide (Abeta) aggregation, and amyloid formation. Abeta.copper complexes have been identified in AD and catalytically oxidize cholesterol and lipid to generate H2O2 and lipid peroxides. The site and mechanism of this abnormality is not known. Growing evidence suggests that amyloidogenic processing of the beta-amyloid precursor protein (APP) occurs in lipid rafts, membrane microdomains enriched in cholesterol. beta- and gamma-secretases, and Abeta have been identified in lipid rafts in cultured cells, human and rodent brains, but the role of copper in lipid raft amyloidogenic processing is presently unknown. In this study, we found that copper modulates flotillin-2 association with cholesterol-rich lipid raft domains, and consequently Abeta synthesis is attenuated via copper-mediated inhibition of APP endocytosis. We also found that total cellular copper is associated inversely with lipid raft copper levels, so that under intracellular copper deficiency conditions, Abeta.copper complexes are more likely to form. This explains the paradoxical hypermetallation of Abeta with copper under tissue copper deficiency conditions in AD.

Serum amyloid P component induces neuronal apoptosis and β-amyloid immunoreactivity

Previously we have reported serum amyloid P component (SAP) induced cell death in cerebro-cortical cultures of rat brain. In this paper we studied the types of target cells and the molecular mechanism of SAP-induced cell death. Immuno-electron and light microscopy revealed that SAP penetrates the plasma membrane and translocates selectively into the nuclei of neurons. Neuronal cells with SAP immunoreactivity exhibit the morphological hallmarks of apoptosis in vitro. The apoptotic mechanism of cell death is also supported by the increased Bax/Bcl-2 ratio. In addition to neurotoxic effects, we detected elevated β-amyloid (Aβ) immunoreactivity following SAP treatment. This study supports the thesis that SAP plays an important role in the pathomechanism of neurodegenerative diseases, including Alzheimer’s disease by inducing neuronal apoptosis.