title: Decreased axonal transport rates in the Tg2576 APP transgenic mouse: improvement with the gamma-secretase inhibitor MRK-560 as detected by manganese-enhanced MRI.
abstract: Neuropil deposition of beta-amyloid (Aβ) peptides is believed to be a key event in the neurodegenerative process of Alzheimer's disease (AD). An early and consistent clinical finding in AD is olfactory dysfunction with associated pathology. Interestingly, transgenic amyloid precursor protein (Tg2576) mice also show early amyloid pathology in olfactory regions. Moreover, a recent study indicates that axonal transport is compromised in the olfactory system of Tg2576 mice, as measured by manganese-enhanced magnetic resonance imaging (MEMRI). Here we tested whether the putative axonal transport deficit in the Tg2576 mouse model improves in response to a selective gamma-secretase inhibitor, N-[cis-4-[(4-chlorophenyl)-sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide (MRK-560). Tg2576 mice or wild-type (WT) littermates were treated daily with MRK-560 (30 μmol/kg) or vehicle for 4 (acute) or 29 days (chronic). The subsequent MEMRI analysis revealed a distinct axonal transport dysfunction in the Tg2576 mice compared with its littermate controls. Interestingly, the impairment of axonal transport could be fully reversed by chronic administration of MRK-560, in line with the significantly lowered levels of both soluble and insoluble forms of Aβ found in the brain and olfactory bulbs (OBs) following treatment. However, no improvement of axonal transport was observed after acute treatment with MRK-560, where soluble but not insoluble forms of Aβ were reduced in the brain and OBs. The present results show that axonal transport is impaired in Tg2576 mice compared with WT controls, as measured by MEMRI. Chronic treatment in vivo with a gamma-secretase inhibitor, MRK-560, significantly reduces soluble and insoluble forms of Aβ, and fully reverses the axonal transport dysfunction.
authors.affiliation: AstraZeneca Research and Development, Innovative Medicines, SE-15185 Södertälje, Sweden. fu-hua.wang@astrazeneca.com
authors.forename: Fu-Hua
authors.initials: FH
authors.lastname: Wang
authors.forename: Paulina
authors.initials: P
authors.lastname: Appelkvist
authors.forename: Tomas
authors.initials: T
authors.lastname: Klason
authors.forename: Olle
authors.initials: O
authors.lastname: Gissberg
authors.forename: Anna
authors.initials: A
authors.lastname: Bogstedt
authors.forename: Kristina
authors.initials: K
authors.lastname: Eliason
authors.forename: Stefan
authors.initials: S
authors.lastname: Martinsson
authors.forename: Sveinn
authors.initials: S
authors.lastname: Briem
authors.forename: Anders
authors.initials: A
authors.lastname: Andersson
authors.forename: Sandra A G
authors.initials: SA
authors.lastname: Visser
authors.forename: Magnus
authors.initials: M
authors.lastname: Ivarsson
authors.forename: Mattias
authors.initials: M
authors.lastname: Lindberg
authors.forename: Karin
authors.initials: K
authors.lastname: Agerman
authors.forename: Johan
authors.initials: J
authors.lastname: Sandin
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D001370:Axonal Transport / Q000187:drug effects* / Q000235:genetics; D001921:Brain / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008345:Manganese; D051379:Mice; D008822:Mice, Transgenic; D009830:Olfactory Bulb / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D016564:Amyloid beta-Protein Precursor; C510791:MRK 560; D013449:Sulfonamides; D008345:Manganese; D053829:Amyloid Precursor Protein Secretases