APP is an integral Type-I transmembrane protein present in several cell types [
51,
52,
53,
54,
55,
56]. It is concentrated in synapses and takes part in cell-matrix and cell-cell interaction in neurons [
19,
57]. This adhesion molecule also participates in various processes in different tissues, for example, APP is involved in hemostasis, thrombosis, sperm motility and sperm-oocyte interaction [
58,
59]. The Aβ hypothesis was formulated, suggesting that an imbalance between production and clearance of Aβ (Aβ dyshomeostasis) is an early, often initiating factor in AD [
60]. However, Aβ plaques were sometimes present in cognitively normal individuals and in the meanwhile neuronal death also occurred in brain regions devoid of plaques [
61]. Oligomers of Aβ peptides are toxic to brain cells and there is no direct correlation between the manifestation of the disease and plaque burden [
62]. The most common view is that increased concentrations of Aβ oligomers trigger neuronal dysfunction and network alterations, with secondary damage produced by hyperphosphorylated tau protein aggregated in tangles [
63,
64]. APP exists in several alternatively spliced isoforms, APP
695, APP
751, and APP
770. The major APP isoforms result from alternative splicing of exon 7 that encodes a Kunitz serine protease inhibitor domain (KPI), exon 8 that codes for a domain with homology to the MRC OX-2 antigen (OX-2) and exon 15. The APP
695 isoform, which lacks the KPI (APP-KPI) and OX-2 domains, is expressed predominantly in neuronal cells. Peripheral cells and platelets, preferably express APP isoforms that contain the KPI domain (APP-KPI
+), including APP
751 (lacking the OX-2 domain) and APP
770 (expressing all exons) [
65,
66,
67,
68]. APP is cleaved by sequential actions of α-, β-, and γ-secretases [
69]. Most of the APP protein is processed by α-secretases in the non-amyloidogenic pathway, which involves cleavage within the Aβ sequence [
70]. α-secretase enzymes belong to the family of disintegrin and metalloprotease including ADAM-10 and ADAM-17 [
71,
72].This process takes place in the secretory pathway, at the plasma membrane and in secretory vesicles. ADAM-10 exerts the major part of the α-secretase activity. It generates the neuroprotective and neurotrophic soluble ectodomain fragment 100–130 kDa (sAPP-α) and non-neurotoxic membrane-associated carboxy-terminal fragments (CTFα or C83) [
73,
74,
75,
76,
77]. Alternatively, APP is processed by β-secretase at the amino terminus of Aβ parts releasing the soluble N-terminal fragment, sAPP-β and a carboxy-terminal fragment (CTFβ or C-99) through the amyloidogenic pathway [
20,
78]. β-site APP-cleaving enzyme 1 (BACE1) is a Type I transmembrane aspartic proteases and has been reported to exert β-secretase activity [
79]. APP CTFα/β is cleaved at the ε-site by the γ-secretase complex, a membrane-embedded multimeric aspartic protease comprising presenilin 1 or 2, nicastrin (NCT), anterior pharynx defective 1 (APH-1), and presenilin enhancer 2 [
80].The γ-secretase action bring to the release of the carboxy-terminal half of APP CTFs, APP intracellular domain (AICD), into the cytosol (6, 7) and secretes the amino-terminal half of APP CTFα/β, p3 and Aβ from APP CTFα and CTFβ respectively [
81,
82,
83,
84]. Following the primary ε-cleavage, further cleavage of the amino-terminal half of APP CTFα/β at multiple γ-sites occurs, and various neurotoxic species of Aβ including Aβ49, Aβ46, Aβ43, and ultimately Aβ40, the major Aβ species, are generated from APP CTFβ [
85]. Alternative cleavage of CTFβ at the minor ε-site results in Aβ48, Aβ45, Aβ42, and, finally, Aβ38, which does not aggregate and is not neurotoxic [
86,
87]. In contrast to neurons that predominantly process APP via the β-secretase pathway, platelets, like other non-neuronal cells, process APP mostly through α-secretase. It has been shown that sAPP concentrations in platelets are much higher than Aβ peptides [
88].