Neuroprotection by cyclodextrin in cell and mouse models of Alzheimer disease

There is extensive evidence that cholesterol and membrane lipids play a key role in Alzheimer disease (AD) pathogenesis. Cyclodextrins (CD) are cyclic oligosaccharide compounds widely used to bind cholesterol. Because CD exerts significant beneficial effects in Niemann-Pick type C disease, which shares neuropathological features with AD, we examined the effects of hydroxypropyl-beta-CD (HP-beta-CD) in cell and mouse models of AD. Cell membrane cholesterol accumulation was detected in N2a cells overexpressing Swedish mutant APP (SwN2a), and the level of membrane cholesterol was reduced by HP-beta-CD treatment. HP-beta-CD dramatically lowered the levels of A beta 42 in SwN2a cells, and the effects were persistent for 24 h after withdrawal. 4 mo of subcutaneous HP-beta-CD administration significantly improved spatial learning and memory deficits in Tg19959 mice, diminished A beta plaque deposition, and reduced tau immunoreactive dystrophic neurites. HP-beta-CD lowered levels of A beta 42 in part by reducing beta cleavage of the APP protein, and it also up-regulated the expression of genes involved in cholesterol transport and A beta clearance. This is the first study to show neuroprotective effects of HP-beta-CD in a transgenic mouse model of AD, both by reducing A beta production and enhancing clearance mechanisms, which suggests a novel therapeutic strategy for AD.