α-Secretase ADAM10 as Well as αAPPs Is Reduced in Platelets and CSF of Alzheimer Disease Patients

Abstract

Background: Members of membrane-bound disintegrin metalloproteinases (ADAMs) were shown to be capable of cleaving amyloid precursor protein (APP) at the ␣cleavage site in different cell systems. One of the candidate ␣-secretases identified in this family is ADAM10. The present study addresses the following major questions: 1) Are the levels of an ␣-secretase candidate (i.e., ADAM10) reduced in accessible cells of Alzheimer Disease (AD) patients? 2) Are ADAM10 levels in the peripheral cells of AD patients related to a concomitant decrease in ␣APPs? Materials and Methods: Western Blot analysis of ADAM10 is performed on platelet homogenates from 33 sporadic AD patients and on 26 age-matched control subjects. Moreover, the levels of ␣-secretase metabolite (␣APPs) are tested both in platelets and cerebrospinal

Translational Repression of the Disintegrin and Metalloprotease ADAM10 by a Stable G-quadruplex Secondary Structure in Its 5′-Untranslated Region

“…Interestingly, nucleolin interacts with G-rich sequences in UTRs or the coding region of a lot of mRNAs and was found to enhance their translation (89), suggesting that nucleolin might function as a RNA-G-quadruplex interacting factor. ADAM10 expression and activity is reduced in platelets and neurons of Alzheimer disease patients (90,91). Translational repression of ADAM10 might be one possible explanation for this observation.…”

Glutamate transporters in platelets: EAAT1 decrease in aging and in Alzheimer’s disease

“…On the basis of these results we suppose that systemic glutamate transporter modifications might explain the decrease of glutamate uptake, that we previously described in platelets from AD patients, and we propose this peripheral model as marker of CNS excitotoxicity. In fact in platelet, as in SNC, APP metabolism alterations [4,9,20,41], mitochondrial dysfunctions [25] and oxidative processes have been described [26].…”

“…Aliquots of cell and tissue extracts were subjected to 7.5% SDS-polyacrylamide gel electrophoresis (PAGE) and transferred to nitrocellulose. To separate cytoplasmic and membrane fractions, platelet pellets were suspended in 1 M HEPES buffer containing 100 mM EGTA, 1 M MgCl 2 , 20 ug/ml Aprotinine, 20 ug/ml Leupeptine, 10 mM Antipaine, 0.1 mM PMSF at 4 • C for 30 min, and then centrifuged at 5 × 10 4 g for 60 min at 4 • C (minor modifications by Colciaghi, [9]). Proteins obtained from sub-fractions were also subjected to SDS-PAGE, as previously described.…”

“…Moreover, in AD they were recently proposed as CNS model to study molecular amyloid-precursor protein (APP) alterations [9]. A high affinity glutamate uptake, with kinetic characteristics similar to brain synaptosomes, was also shown in platelets, which appear the major site of clearance of glutamate from blood [34].…”

MicroRNA-144 Is Regulated by Activator Protein-1 (AP-1) and Decreases Expression of Alzheimer Disease-related A Disintegrin and Metalloprotease 10 (ADAM10)

“…This alternative processing of APP by ␣-secretase generates the neuroprotective and neurotrophic soluble APPs␣ ectodomain (4). ADAM10, whose level is decreased in the platelets and neurons of AD patients (5,6), is the most recognized candidate for ␣-secretase in cell culture and mouse models (7)(8)(9). Additionally, APPs␣ is also decreased in the cerebrospinal fluid of AD patients (10,11), indicating a reduced amount and/or activity of ADAM10.…”