Analysis of the relationship between Amyloid β protein and cholesterol in Alzheimer's disease.

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Alzheimer's disease (AD) is one of the most frequent neurodegenerative disorders in elder people. Familial AD is known to be caused by mutations in the amyloid β protein precursor (APP), Presenilin 1 or 2, though these causes of AD are relatively uncommon. But those genetic risk factors account for less than 2% of all AD causes, remaining are sporadic AD.Amyloid β protein (Aβ) is one of the abnormally accumulated proteins in AD's brain. Aβ fibril formation and deposition long have been linked to the neuropathogenesis of AD. And abnormal processing of APP and increase in Aβ may play a major role in the pathogenesis of the hereditary forms and also that of sporadic AD.We investigate the relationship between APP, Aβ and cholesterol to find the evidence that cholesterol may play a role in the cleavage of APP. We made APP-overexpressed CHO cells and npc1 defected CHO (nCHO) cells by transfect the wild type, Swedish and Tottori (D678N) type mutated APP. Npc1 is defected in Niemann-Pick disease type C, which has lack in intracellular transport and maintenance of homeostasis of cholesterol. We analyzed intracellular quantity, synthesis and esterification of cholesterol, but excess APP had no effects directly. Then we determined intracellular APP levels and production Aβ in different intracellular cholesterol background using both cells with extracellular stimulation of Aluminum, LDL and oxidative stress.Despite no relationship APP, Aβ and Aluminum, more sensitive against Aluminum in nCHO cells compared normal cells. Exposure of excess LDL induced the cleavage of APP by β-secretase in nCHO cells, which indicated Aβ production. Intracellular APP levels on the oxidative stress were decreased in CHO cells but not affected in nCHO. Fewer lipids in nCHO of membrane in nCHO may prevent the oxidative attack against cell membrane.The disruption of cholesterol homeostasis might accelerate and strengthen the risks in AD.