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.

Axonal degeneration in an Alzheimer mouse model is PS1 gene dose dependent and linked to intraneuronal Aβ accumulation

“…However, in recent years, similar phenotypes have been reported for AD mouse models based on APP overexpression (Stokin et al, 2005; Wirths et al, 2006, 2007; Adalbert et al, 2009; Jawhar et al, 2012) and disturbances of axonal transport rates have been reported in APP-based transgenic mouse models of Down syndrome (Salehi et al, 2003) and AD (Smith et al, 2007; Kim et al, 2011; Wang et al, 2012). Accordingly, APP has been demonstrated to undergo fast axonal transport (Koo et al, 1990), presumably by a kinesin-I-mediated mechanism (Kamal et al, 2000), and the β-site cleaving enzyme (BACE) and PS1 have been shown to be associated with APP-resident membranous cargos.…”

In vivo axonal transport deficits in a mouse model of fronto-temporal dementia

“…MEMRI utilizes the presence of Ca 2 + channels in neurons in order to enter cells and be transported down their axons (Inoue et al, 2011). MEMRI has many applications and has been used to measure rates of transport in models of both hyperglycemia as well as Alzheimer's disease (Kim et al, 2009) (Fu-Hua Wang, 2012). MEMRI can also be used to measure synaptic strength in vivo (Serrano et al, 2008).…”

Laminar specific detection of APP induced neurodegeneration and recovery using MEMRI in an olfactory based Alzheimer's disease mouse model

“…The Tg2576 Alzheimer’s mouse model is shown to exhibit Aβ depositions in the OB earlier than in other brain regions, with a decrease in olfactory function (Wesson et al, 2010, Wesson et al, 2011). This animal model was later used to measure axonal transport rates into the OB using MEMRI (Smith et al, 2007, Wang et al, 2012). Following Mn 2+ administration to the mice nostrils, the rates of manganese transport from the OSNs to the OB layers were calculated and showed a decrease in transport rates during progression of Aβ accumulation (Smith et al, 2007).…”