title: Neuroprotection by cyclodextrin in cell and mouse models of Alzheimer disease.
abstract: 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-β-CD (HP-β-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-β-CD treatment. HP-β-CD dramatically lowered the levels of Aβ42 in SwN2a cells, and the effects were persistent for 24 h after withdrawal. 4 mo of subcutaneous HP-β-CD administration significantly improved spatial learning and memory deficits in Tg19959 mice, diminished Aβ plaque deposition, and reduced tau immunoreactive dystrophic neurites. HP-β-CD lowered levels of Aβ42 in part by reducing β cleavage of the APP protein, and it also up-regulated the expression of genes involved in cholesterol transport and Aβ clearance. This is the first study to show neuroprotective effects of HP-β-CD in a transgenic mouse model of AD, both by reducing Aβ production and enhancing clearance mechanisms, which suggests a novel therapeutic strategy for AD.
authors.affiliation: Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY 10065, USA. jiy2006@med.cornell.edu
authors.forename: Jiaqi
authors.initials: J
authors.lastname: Yao
authors.forename: Daniel
authors.initials: D
authors.lastname: Ho
authors.forename: Noel Y
authors.initials: NY
authors.lastname: Calingasan
authors.forename: Nina H
authors.initials: NH
authors.lastname: Pipalia
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lin
authors.forename: M Flint
authors.initials: MF
authors.lastname: Beal
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control* / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007858:Learning / Q000187:drug effects; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008568:Memory / Q000187:drug effects; D051379:Mice; D057507:Mice, 129 Strain; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000378:metabolism; D058225:Plaque, Amyloid / Q000473:pathology / Q000517:prevention & control; D047392:beta-Cyclodextrins / Q000494:pharmacology*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D047392:beta-Cyclodextrins; D016875:tau Proteins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D002784:Cholesterol