This is consistent with the timescale of disease onset in the mouse model. Prion disease is modelled in mice sellekchem through ME7 prion agent infection resulting in both a behavioural pheno type and synaptopathy. The transcriptional study corresponded to hippocampal profiles for ME7 v normal brain homogenate inoculated mice. Pooling the treatment sets we get a good correlation with the AD profile, see Table 4. Thus it is clear that there is a core response profile shared across many neurodegenerative conditions and animal models of these conditions. Importantly, this core set is charac terised by synaptic pathology and mitochondrial dys function, both of which are hypothesised to be causative of a number of neurodegenerative disease states.

It might be thought that we are getting further away from the specific pathology, in this case AD, and losing transcriptional information that could be of use in the hunt for a therapy. This is however not the case as can be seen when we search the CMAP with a profile com posed of genes whose sense change is conserved across the rodent disease models. Combining the severe AD profile and the four rodent neurodegenerative disease model profiles we get a set of 24 genes whose sense change is conserved. This consists of 10 up regulated and 14 down regulated genes, which can be thought of as a binary signature for neuropathology, where 1 is assigned to up regulated genes and 1 to down regu lated genes, see Table 5. The CMAP drugs with the highest anti correlation with this signature are shown in Table 6. Remarkably, there are at least 9 neuroprotective agents in the top 22 hits.

In particular, Galantamine, a plant alkaloid, is currently prescribed for early stage AD, it was originally studied for its acetylcholinester ase inhibitory activity, but it may also act on other tar gets. The flavones chrysin, apigenin and luteolin have been reported to have neu roprotective activity. As have the two kinase inhibitors H 7 and GW 8510. The b carboline plant Carfilzomib alkaloid harmine has several neuronal actions. It acts to slow down the breakdown of monoamine neurotransmitters through inhibition of monoamine oxidase A. Also, it has been shown to specifically inhibit DYRK1A, an enzyme responsible for phosphorylation of tau and thereby may act to slow tau pathology in AD and DS. Nomi fensine is a dopamine reuptake inhibitor originally pre scribed as an anti depressant that has been shown to reverse dopaminergic neurotoxicity and to have beneficial effects in Parkinsons disease. Carba chol is an acetylcholine receptor agonist, but with poor blood brain barrier penetration. The possible appli cation of the other high scoring compounds remains to be determined.