Pyroglutamate Aβ is formed selleck by truncation of the first two N-terminal amino acids of Aβ and subsequent posttranslational modification of the

third amino acid, glutamate, into pyroglutamate by glutaminyl cyclase. Pyroglutamate Aβ is known to be more prone to aggregate, to form oligomers, and to be more toxic ( Jawhar et al., 2011). Pyroglutamate Aβ is not normally present in vivo; it is, however, found in amyloid plaques ( Saido et al., 1996). Herein, DeMattos et al. (2012) compared the effect of peripherally administered mE8 with effects of monoclonal antibody 3D6, which binds to both soluble and insoluble forms of Aβ in the brain in both preventive and therapeutic paradigms. When administered in a transgenic mouse model (PDAPP) at an age at which there are large amounts of Aβ plaque selleck chemicals pathology in the brain as well as CAA, mE8 strongly decreased the amount of pre-existing, accumulated insoluble Aβ. This effect occurred without an increase in the amount of CAA or microhemorrhages ( Figure 1, right). On

the other hand, the 3D6 antibody did not decrease the amount of insoluble Aβ in the brain in old PDAPP mice with a large amount of pre-existing amyloid plaques, though it markedly increased CAA and CAA-associated microhemorrhages. Interestingly, 3D6 worked well in decreasing amyloid plaques and insoluble Aβ when given in a prevention mode, as has been shown previously ( Figure 1, left). Studies like this, in which a compound is tested in a model in which the amount of Aβ plaques and accumulation in the brain is comparable to what is seen in humans with AD dementia, have not frequently been done in this field. The results strongly suggest that if one is targeting humans in clinical trials who already have substantial amyloid deposition, the design of such trials should be based on preclinical studies that mimic the human disease state that one is targeting.

The preclinical results of DeMattos et al. (2012) would have predicted both little change in plaque load with bapineuzumab in humans and its effect of increasing CAA. Thus, utilizing mouse models can be useful, if similar stages of pathology are being compared to the human condition. When Methisazone administered prior to amyloid plaque formation, mE8 did not prevent Aβ plaque deposition. The lack of efficacy in the prevention trial suggests that mE8 is not working by blocking seeding of soluble forms of Aβ. It does act on already formed Aβ deposits, presumably because pyroglutamate Aβ is generated after initial Aβ aggregation. In future studies, it will be important to combine therapies to both prevent and remove Aβ accumulation, for example, by combining drugs that inhibit Aβ production (e.g., gamma secretase inhibitors/modulators and β-site amyloid precursor protein-cleaving enzyme inhibitors) with therapies that remove existing plaques.