Isomerization of Asp7 leads to increased toxic effect of amyloid-β42 on human neuronal cells

The generation of toxic oligomers during the aggregation of the 42-residue amyloid- β (A β ) peptide A β 42 into amyloid fibrils and plaques has emerged as a central feature of the onset and progression of Alzheimer’s disease (AD). 1 Isomerization of an aspartic acid residue at position 7 is a common chemical modification of A β 42 isolated from brain of the patients diagnosed with AD. 2 This modification crucially influences such processes as zinc ion chelation by A β , 3 zinc-dependent oligomerization of A β , 4 and hydrolysis of A β by the angiotensin-converting enzyme. 5 As each of these molecular events is closely related to the aggregation ability of A β , we have hypothesized that A β 42 containing isoaspartate 7 (isoA β 42) might have a role in the development of cerebral β -amyloidosis. Indeed, recently we have shown that when isoA β 42 is administered into blood of transgenic mice used as an animal model of AD, it accelerates the formation of amyloid plaques in contrast to A β 42, which does not have this effect. 6 Thus, one could rationally suggest that isoA β 42 acts as aggregation seed and/or corruptive template compelling the physiological pool of endogenous A β 42 to be converted into oligomers and consequently into aggregates. To get a deeper insight into the mechanism of isoA β 42 pathogenicity, in the present study a comparison was made of the cytotoxic effect of isoA β 42 and A β 42.