**5. Presenilin substrate APP and production of toxic β-amyloid peptides**

Aβ peptides are generated from amyloid β-precursor protein (APP) by enzymatic digestion involving the activity of α-, β- and γ-secretases. Amyloidogenic cleavage of APP is started by β-secretase, which generates a 100-kDa-soluble N-terminal fragment and membrane-bound 12-kDa C-terminal fragment (C99), which is further cleaved by γ-secretase, yielding the APP intracellular domain (AICD) and 40, 42, up to 56 amino acids Aβ peptides. C99 cleavage by γ-secretase is inaccurate and results in numerous different Aβ species, but those ending at position 40 (Aβ1-40) are the most abundant and considered as physiological (~80–90%), followed by less abundant but toxic 42 (Aβ1–42, ~5–10%). The second cleavage, which takes place within the hydrophobic transmembrane domain (TMD) and is regulated by intramembrane proteolysis (RIP), has been attributed to the γ-secretase complex with presenilins, as the catalytic component. The γ-secretase is a membrane-bound protease complex consisting of four components: nicastrin, anterior pharynx-defective 1 (APH-1) and presenilin enhancer 2 (PEN-2) and presenilin (1 or 2) forming aspartyl protease subunit and activity centre of the complex [40, 41].

As mentioned above, PA patients are characterized by the presence of amyloid deposits. However, PA is manifested by fewer-cored plaques and there is little or no neuritic pathology or neurofibrillary tangles in the cortex. Moreover, the species of Aβ peptides in PA differs from AD brains. It has been demonstrated that Aβ1–40 levels were 20-fold higher in AD brains compared to PA brains, whereas Aβ1–42 levels were only twofold higher [42]. Overall, several studies suggested quantitative and qualitative differences in the amyloid deposits between PA and AD brains [43]. It can be concluded that a wide spectrum of harmful effects of Aβ species, peptides, oligomers or plaques coincides with the disturbed presenilin signalling. These data demonstrate both common and different mechanisms of AD and PA, with the contribution presenilin, whose functions influence qualitative and quantitative status of amyloid.
