Platelets and Alzheimer's disease: Potential of APP as a biomarker - PubMed (original) (raw)

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Platelets and Alzheimer's disease: Potential of APP as a biomarker

Geneviève Evin et al. World J Psychiatry. 2012.

Abstract

Platelets are the first peripheral source of amyloid precursor protein (APP). They possess the proteolytic machinery to produce Aβ and fragments similar to those produced in neurons, and thus offer an ex-vivo model to study APP processing and changes associated with Alzheimer's disease (AD). Platelet process APP mostly through the α-secretase pathway to release soluble APP (sAPP). They produce small amounts of Aβ, predominantly Aβ40 over Aβ42. sAPP and Aβ are stored in α-granules and are released upon platelet activation by thrombin and collagen, and agents inducing platelet degranulation. A small proportion of full-length APP is present at the platelet surface and this increases by 3-fold upon platelet activation. Immunoblotting of platelet lysates detects APP as isoforms of 130 kDa and 106-110 kDa. The ratio of these of APP isoforms is significantly lower in patients with AD and mild cognitive impairment (MCI) than in healthy controls. This ratio follows a decrease that parallels cognitive decline and can predict conversion from MCI to AD. Alterations in the levels of α-secretase ADAM10 and in the enzymatic activities of α- and β-secretase observed in platelets of patients with AD are consistent with increased processing through the amyloidogenic pathway. β-APP cleaving enzyme activity is increased by 24% in platelet membranes of patients with MCI and by 17% in those with AD. Reports of changes in platelet APP expression with MCI and AD have been promising so far and merit further investigation as the search for blood biomarkers in AD, in particular at the prodromal stage, remains a priority and a challenge.

Keywords: Alzheimer’s disease; Amyloid precursor protein; Aβ amyloid; Biomarker; Platelet; Protease-nexin 2; Secretase; β-amyloid precursor protein cleaving enzyme.

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Figures

Figure 1

Figure 1

Schematic diagram of the amyloid precursor protein. The diagram represents the structural domain arrangement of the amyloid precursor protein (APP) gene products. All domains are expressed in the APP770 isoform. The OX-2 domain is missing in APP751, whereas both the Kunitz protease inhibitor domain (KPI) and the OX-2 domain are missing in APP695. SP: Signal peptide; E1: Ectodomain 1; E2: Ectodomain 2; TMD: Transmembrane domain; CD: Cytosolic domain; OX-2: Domain with homology to OX-2 leukocyte antigen; Ex 15: Exon 15 product; HB: Heparin-binding domain; MB: Metal ion-binding domain.

Figure 2

Figure 2

Proteolytic processing of amyloid precursor protein by the secretases. In a non-amyloidogenic pathway, α-secretase cleaves amyloid precursor protein (APP) within the Aβ domain to release the α-cleaved soluble N-terminal fragment, sAPPα. β-Amyloid precursor cleaving enzyme (BACE) cleaves APP at the N-terminus of Aβ to release the β-cleaved soluble N-terminal fragment sAPPβ, and thereby initiates the amyloidogenic pathway. The remaining 99 amino acid-long C-terminal fragment (C99) is further processed at multiple sites by γ-secretase to release the APP intracellular domain (AICD) in the cytosol and Aβ peptides in the extracellular space.

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References

    1. Querfurth HW, LaFerla FM. Alzheimer's disease. N Engl J Med. 2010;362:329–344. - PubMed
    1. Reitz C, Brayne C, Mayeux R. Epidemiology of Alzheimer disease. Nat Rev Neurol. 2011;7:137–152. - PMC - PubMed
    1. Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci USA. 1985;82:4245–4249. - PMC - PubMed
    1. Glenner GG, Wong CW. Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun. 1984;120:885–890. - PubMed
    1. Goedert M. Tau protein and the neurofibrillary pathology of Alzheimer's disease. Trends Neurosci. 1993;16:460–465. - PubMed

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