The processing of the amyloid precursor protein (APP) is a critical event in the formation of amyloid plaques. Platelets contain most of the enzymatic machinery required for APP processing and correlates of intracerebral abnormalities have been demonstrated in platelets of patients with AD. The goal of the present paper was to analyze studies exploring platelet APP metabolism in Alzheimer's disease patients trying to assess potential reliable peripheral biomarkers, to offer new therapeutic solutions and to understand the pathophysiology of the AD. According to the PRISMA guidelines, we performed a systematic review through the PubMed database up to June 2020 with the search terms: "((((((APP) OR Amyloid Precursor Protein) OR AbetaPP) OR Beta Amyloid) OR Amyloid Beta) OR APP-processing) AND platelet". Thirty-two studies were included in this systematic review. The papers included are analytic observational studies, namely twenty-nine cross sectional studies and three longitudinal studies, specifically prospective cohort study. The studies converge in an almost unitary way in affirming that subjects with AD show changes in APP processing compared to healthy age-matched controls. However, the problem of the specificity and sensitivity of these biomarkers is still at issue and would deserve to be deepened in future studies.

The clinical diagnosis of Alzheimer's disease (AD) is a probabilistic formulation that may lack accuracy particularly at early stages of the dementing process. Abnormalities in amyloid-beta precursor protein (APP) metabolism and in the level of APP secretases have been demonstrated in platelets, and to a lesser extent in leukocytes, of AD patients, with conflicting results. The aim of the present study was to compare the protein level of the APP secretases A-disintegrin and metalloprotease 10 (ADAM10), Beta-site APP-cleaving enzyme 1 (BACE1), and presenilin-1 (PSEN1) in platelets and leukocytes from 20 non-medicated older adults with AD and 20 healthy elders, and to determine the potential use of these biomarkers to discriminate cases of AD from controls. The protein levels of all APP secretases were significantly higher in platelets compared to leukocytes. We found statistically a significant decrease in ADAM10 (52.5%, p < 0.0001) and PSEN1 (32%, p = 0.02) in platelets from AD patients compared to controls, but not in leukocytes. Combining all three secretases to generate receiver-operating characteristic (ROC) curves, we found a good discriminatory effect (AD vs. controls) when using platelets (the area under the curve-AUC-0.90, sensitivity 88.9%, specificity 66.7%, p = 0.003), but not in leukocytes (AUC 0.65, sensitivity 77.8%, specificity 50.0%, p = 0.2). Our findings indicate that platelets represent a better biological matrix than leukocytes to address the peripheral level of APP secretases. In addition, combining the protein level of ADAM10, BACE1, and PSEN1 in platelets, yielded a good accuracy to discriminate AD from controls.

Presenilin (PS)-1 is an intramembrane protease serving as the catalytic component of γ-secretase. Mutations in the PS1 gene are the most common cause of familial Alzheimer's disease (FAD). The low-density lipoprotein (LDL)-receptor family member apoER2 is a γ-secretase substrate that has been associated with AD in several ways, including acting as a receptor for apolipoprotein E (ApoE). ApoER2 is processed by γ-secretase into a C-terminal fragment (γ-CTF) that appears to regulate gene expression. FAD PS1 mutations were tested for effects on apoER2. PS1 mutation R278I showed impaired γ-secretase activity for apoER2 in the basal state or after exposure to Reelin. PS1 M146V mutation permitted accumulation of apoER2 CTFs after Reelin treatment, whereas no difference was seen between wild-type (WT) and M146V in the basal state. PS1 L282V mutation, combined with the γ-secretase inhibitor N-(N-[3,5-Difluorophenacetyl]-L-alanyl)-S-phenylglycine t-butyl ester, greatly reduced the cell-surface levels of apoER2 without affecting total apoER2 levels, suggesting a defect in receptor trafficking. These findings indicate that impaired processing or localization of apoER2 may contribute to the pathogenic effects of FAD mutations in PS1.

In this study we show that both glycogen synthase kinase 3 (GSK3) isoforms, GSK3alpha and GSK3beta, are present in human platelets and are phosphorylated on Ser(21) and Ser(9), respectively, in platelets stimulated with collagen, convulxin and thrombin. Phosphorylation of GSK3alpha/beta was dependent on phosphoinositide 3-kinase (PI3K) activity and independent of platelet aggregation, and correlated with a decrease in GSK3 activity that was preserved by pre-incubating platelets with PI3K inhibitor LY294002. Three structurally distinct GSK3 inhibitors, lithium, SB415286 and TDZD-8, were found to inhibit platelet aggregation. This implicates GSK3 as a potential regulator of platelet function.

A growing body of evidence indicates that presenilins could exist and be active as oligomeric complexes. Using yeast two-hybrid and cell culture analysis, we provide evidence that presenilin-1 (PS1) may self-oligomerize giving rise to specific full-length/full-length homodimers. When expressed in N2A and HEK239T cultured cells, full-length PS1-wt and 5(')myc-PS1-wt form specific homodimers corresponding to twice their molecular weight. The Alzheimer's disease-associated PS1 mutations Y115H, M146L, L392V, deltaE10(PS1(1-289/320-467)), the gamma-secretase dominant negative mutant D257A, and the PS1 polymorphism mutant E318G do not affect their ability to self-oligomerize. Under non-denaturing conditions, endogenous PS1 forms specific homo-oligomers in human cultured cells. The results obtained herein suggest that PS1 associates intramolecularly to form higher order complexes, which may be needed for endoproteolytic cleavage and/or gamma-secretase-associated activity.

Most cases of familial Alzheimer disease (AD) are caused by mutations in presenilin 1 (PS1) and presenilin 2 (PS2). Presenilins are required for the proteolytic processing of the beta amyloid precursor protein, which yields beta amyloid peptide, the major component of extracellular amyloid plaques. In addition, presenilins are essential for proteolytic processing of other membrane proteins, including Notch, TrkB, and APLP2. Notch directs neural and hematopoietic development. Here we show mRNA and protein expression of PS1 in both lymphoid and myeloid cells, while PS2 mRNA is present only in lymphocytes. Expression of PS1 was found throughout myeloid development from CD34+ stem cells to platelets and neutrophils. PS1 expression was found in avian as well as mammalian blood cells. In neutrophils, PS1 colocalized with myeloperoxidase and CD63 within the azurophil granules as demonstrated by subcellular fractionation and double labeling immunogold electron microscopy. In platelets, PS1 colocalized with glucose transporter (GLUT-3) in the membrane of alpha granules, as evidenced by immunogold electron microscopy. The colocalization of PS1 and amyloid precursor protein in cell-specific granules suggests a conserved function across different tissues. These studies indicate that PS1 may play multiple roles in blood cell physiology and that blood tissue may provide a model to study PS1 interactions with other proteins.

It is well known that presenilin-1 (PS1) is involved in cleavage of amyloid precursor protein (APP) at the gamma-secretase site, and that the amino acids residues of D257 and D385 in PS1 are critical for this cleavage of APP and the endoproteolysis of itself. An alternatively spliced form of PS1 skipping exon 8 (PS1d8), which has D257A at the splice junction of exon 7/9, is expressed in human brain and in some cell lines. In this study, we examined production of Amyloid beta (A beta) and the endoproteolysis of the holoproteins in PS1d8-expressing neuroblastoma cells. Western blotting showed an absence of endoproteolysis in PS1d8. However, PS1d8 did not affect the production of A beta, which is different from the artificial point mutant PS1D257A. These results suggest that endoproteolysis of PS1 and gamma-secretase activity could be independent.

Mutations in the presenilin genes (PS-1 and PS-2) cause early onset autosomal dominant Alzheimer's disease (AD). Eight early-onset, autopsy-documented familial AD kindreds were screened for mutations in PS-1, and seven different mutations were identified. Three of these were new mutations (G209V, A426P, and E120D), two were previously reported mutations in new families, and three mutations were confirmed in previously published families. Two of these new mutations are found within predicted transmembrane domains (TMDs 4, 7, and 8). The A426P mutation is the most C-terminal PS-1 mutation identified to date.

Mutations in the presenilin-1 (PS-1) and presenilin-2 (PS-2) genes account for the majority of cases of early-onset familial Alzheimer's disease (AD). Alternative splicing forms of the PS-1 and PS-2 gene products have previously been reported in fibroblast and brain tissue from both familial and sporadic AD patients, as well as from normal tissues and cell lines. We demonstrate here unusual alternative splicing of the PS-2 gene that leads to the generation of mRNA lacking exon 5 in human brain tissue. This product was more frequently detected in brain tissue from sporadic AD patients (70.0%; 21 of 30) than from normal age-matched controls (17.6%; three of 17). In cultured neuroblastoma cells, this splice variant was generated in hypoxia but not under other forms of cellular stress. Hypoxia-mediated induction of this splice variant was blocked by pretreatment of neuroblastoma cells with the protein synthesis inhibitor cycloheximide or antioxidants such as N-acetylcysteine and diphenyl iodonium, suggesting that hypoxia-mediated oxidant stress might, at least in part, underlie the alternative splicing of PS-2 mRNA through de novo protein synthesis. Furthermore, the stable transfectants of this splice variant produced the N-terminal part of PS-2 protein (15 kDa) and were more susceptible to cellular stresses than control transfectants. These results suggest the possibility that altered presenilin gene products in stress conditions may also participate in the pathogenesis of AD.

Expression of presenilin-1 (PS-1) mRNA in an alternative splicing at the 3' end of exon 3 was examined in brain tissue, lymphocytes and cultured skin fibroblasts using the RT- polymerase chain reaction (RT-PCR) method. We quantified the relative ratios of the densities of the long form of PS-1 mRNA, which contains a sequence encoding four amino acids (VRSQ, denoted as VRSQ+) to the short form, which lacks the VRSQ sequence (VRSQ-). The brain tissue of subjects with sporadic Alzheimer's disease (AD) had reduced levels of the VRSQ+ form of the PS-1 mRNA compared to a control group. No significant differences appeared in peripheral tissues, such as lymphocytes or cultured skin fibroblasts in AD with control subjects. Changes in the alternative splicing of exon 3 may be specific to the brain and may play an important role in the pathogenesis of sporadic AD.