Schematic of amyloid precurser protein metabolism, from which amyloid β peptide can be produced. The amyloid precurser protein (APP) amino acid sequence is given in the single letter code with the boxed sequence representing the amyloid β peptide (Aβ). The red arrows denoted by β and γ represent the major β- and γ-secretase cleavage sites on APP from which Aβ is produced in the amyloidogenic pathway. The green arrow denoted by α pointing to the highlighted lettering shows the vicinity of the major α-secretase site on APP, which precludes the formation of APP in the anti-amyloidogenic pathway. The blue arrows labelled ACE show the proposed amino acids that are involved in (anti-amyloidogenic denoted by a question mark) ACE-mediated cleavage of Aβ, which were suggested to be either Asp7-Ser8 based on the detection of Aβ8–40 fragments or Arg5-His6 [8, 32]. Interestingly, isomerisation (that is, having the same molecular formula but having a different structure and sometimes different properties) of the Asp7 (isoAsp7) residue of Aβ, a common age-related and possible conformational modification that is more prevalent in Alzheimer's disease (AD), resulted in more efficient cleavage than the non-modified Asp7 in vitro. It has thus been suggested that the main cleavage site of angiotensin-1 converting enzyme could be Arg5-His6 and the identification of Aβ8–40 cleavage products detected previously might be the result of subsequent hydrolysis of Aβ6–40 fragments. The blue horizontal arrows of different sizes and pointing in opposite directions indicate that the majority of APP processing throughout a lifetime is anti-amyloidogenic but that in AD there is evidence of some increased amyloidogenic processing (denoted by the dashed arrow). Negative effects on the cholinergic pathway resulting from Aβ activity are shown, as are reported complex feedbacks between cholinergic receptors and APP processing (see  for a review). ChAT, choline acetyltransferase.