Role of a mouse ortholog of CR1 (crry) in the 3xTG model of Alzheimer’s Disease (AD)
This research project is in competition for funding with one or more projects available through the UK Dementia Research Institute (DRI) at Cardiff. Usually the projects which receive the best applicants will be awarded the funding. Find out more information about the UK DRI and how to apply.
In order to explore further roles of Crry, we have generated and established a 3xTG/Crry-/- colony, but have not yet had resources to explore further the impact of Crry deficiency in this model.
Several genes of the pro-inflammatory complement system, including CR1, Cr1L, Clu and C3 have been linked to AD. However, there remains a yawning gap in our understanding of how proteins derived from these genes impact risk of AD. In rodents, the closest genetic ortholog to CR1 is the broadly expressed C3 convertase regulator Crry (Cr1-related protein Y).
Crry gene deletion is embryonic lethal; we rescued Crry-/- pups by inhibiting complement in pregnant dams and established a unique Crry-/- line (Ruseva et al 2009 PMID:18947875).
The mice were grossly normal but displayed a 'primed' microglial phenotype, Tau hyperphosphorylation and increased brain cytokine expression (Ramaglia et al 2012 PMID:22219359; Killick et al 2013 PMID:23153828).
Project aims and methods
Based on our published studies, we hypothesise that deletion of Crry, by creating a pro-inflammatory state in the brain, will accelerate and exacerbate pathological changes and cognitive decline.
To test this hypothesis we will:
- assess disease and inflammatory markers, including complement, by IHC in brains obtained from 3xTG/Crry-/- and 3xTG/Crry+/+ controls at various ages from 3 to 18 months
- assess behaviour and cognition in 3xTG/Crry-/- and 3xTG/Crry+/+ mice at different ages, applying a raft of state-of-the-art tests of cognition, emotion, anxiety, social interaction and motor function
- extract RNA from micro-dissected brains (hippocampus, neo-cortex etc.) from 3xTG/Crry-/- and 3xTG/Crry+/+ mice at different ages to assess by qPCR spatial and temporal differences in expression of inflammatory (including complement) and disease-associated genes. subjected to AD targeted qPCR arrays, and confirm cellular sources of genetic hits using in situ hybridisation and/or laser microdissection
- test impact on course of disease of inhibiting complement dysregulation using a complement inhibitor selected from our toolkit guided by findings in earlier aims to target the relevant pathway or effector.
A minimum of a 2.1 or master's in a relevant degree subject is required. Relevant degrees subjects include, for example:
- cell biology
- and related disciplines.