The amyloid precursor protein of Alzheimer's disease is released by human platelets.

Bush, Ashley I.; Martins, Ralph N.; Rumble, Baden; Moir, Robert D.; Fuller, Stephanie J.; Milward, Elizabeth A.; Currie, Jay D.; Ames, David; Weidemann, Andreas; Fischer, P.

doi:10.1016/s0021-9258(18)55493-4

Cited by 310 publications

(36 citation statements)

References 47 publications

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“…inhibitor (10 mM inhibitor IV, Merck) in medium containing 20% bovine serum that is known to contain full length APP. 3,4 The endothelium as a source of APP, however, cannot be ruled out. The Western blot data indicate an increase in the expression of both the mature APP and the soluble APP-a (sAPP-a) isoforms in the medium upon BACE-1 inhibition (Figure 3d).…”

Section: Localization and Activity Of Bace-1 At The Bbbmentioning

confidence: 99%

“…A significant amount of APP is present in the peripheral circulation, that is expressed by platelets and more prone to toxic Ab formation than the neuronal form of APP in the brain parenchyma. 3,4 Platelet-derived APP contains the Kunitz Protease Inhibitor (KPI) domain that favors aggregation of amyloid peptides, resulting from the cleavage of APP. 5 Moreover, there are reports correlating an increase in KPI domain containing APP in the circulation with incidence and severity of AD in humans.…”

Section: Introductionmentioning

confidence: 99%

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BACE-1 is expressed in the blood–brain barrier endothelium and is upregulated in a murine model of Alzheimer’s disease

Devraj

Poznanović²,

Spahn

et al. 2015

J Cereb Blood Flow Metab

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Endothelial cells of the blood-brain barrier form a structural and functional barrier maintaining brain homeostasis via paracellular tight junctions and specific transporters such as P-glycoprotein. The blood-brain barrier is responsible for negligible bioavailability of many neuroprotective drugs. In Alzheimer's disease, current treatment approaches include inhibitors of BACE-1 (b-site of amyloid precursor protein cleaving enzyme), a proteinase generating neurotoxic b-amyloid. It is known that BACE-1 is highly expressed in endosomes and membranes of neurons and glia. We now provide evidence that BACE-1 is expressed in blood-brain barrier endothelial cells of human, mouse, and bovine origin. We further show its predominant membrane localization by 3D-dSTORM super-resolution microscopy, and by biochemical fractionation that further shows an abluminal distribution of BACE-1 in brain microvessels. We confirm its functionality in processing APP in primary mouse brain endothelial cells. In an Alzheimer's disease mouse model we show that BACE-1 is upregulated at the blood-brain barrier compared to healthy controls. We therefore suggest a critical role for BACE-1 at the blood-brain barrier in b-amyloid generation and in vascular aspects of Alzheimer's disease, particularly in the development of cerebral amyloid angiopathy.

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Section: Localization and Activity Of Bace-1 At The Bbbmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

BACE-1 is expressed in the blood–brain barrier endothelium and is upregulated in a murine model of Alzheimer’s disease

Devraj

Poznanović²,

Spahn

et al. 2015

J Cereb Blood Flow Metab

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“…Despite different embryonic origin, both platelets and neurons exhibit the same responses in many neurological and mental disorders, such as Alzheimer's diseases, Parkinson's diseases, various forms of schizo phrenia, and depression [25]. For example, platelets express large amounts of APP (amyloid precursor pro tein); the highest concentration of this protein was found in the brain and in platelets [28]. It was suggested that changes observed in the brain in Alzheimer's diseases are reflected in platelets [29].…”

Section: Monoamine Oxidasementioning

confidence: 99%

Monoamine Oxidase as a Potential Biomarker of the Efficacy of Treatment of Mental Disorders

Узбеков

2021

Biochemistry Moscow

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The review summarizes the results of our own studies and published data on the biological markers of psychiatric disorders, with special emphasis on the activity of platelet monoamine oxidase. Pharmacotherapy studies in patients with the mixed anxiety-depressive disorder and first episode of schizophrenia have shown that the activity of platelet monoamine oxidase could serve as a potential biomarker of the efficacy of therapeutic interventions in these diseases.

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“…The APP isoform with the Kunitz type II protease inhibitor domain, APP751/770, has been historically described as protease nexin-2, a membrane protein and a-granule protein in platelets (22,25). Nevertheless, intracellular localization of membrane-bound APP remains unclear.…”

Section: App770 Is Expressed On the Platelet Surface And Is Released Upon Platelet Activationmentioning

confidence: 99%

“…APP has three kinds of alternatively spliced mRNA isoforms: APP695, APP751, and APP770 (18,19). APP695 is predominantly expressed in neurons (20), whereas APP770 is found in vascular endothelial cells (21) and platelets (22). The soluble form of APP770 (sAPP770) is released upon platelet activation, and plasma sAPP770 levels are significantly higher in ACS patients (23).…”

mentioning

confidence: 99%

Amyloid precursor protein 770 is specifically expressed and released from platelets

Miura

Yoshihisa

Misaka

et al. 2020

Journal of Biological Chemistry

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Platelets not only play an essential role in hemostasis after vascular injury, but are also involved in the development of coronary artery disease (CAD) and cerebrovascular lesions. Patients with CAD and cerebral ischemia are recommended to undergo antiplatelet therapy, but they have an increased incidence of major bleeding complications. Both assessment of the platelet activation status and response to antiplatelet therapy in each patient are highly desired. Amyloid β-precursor protein (APP) 770 is expressed in vascular endothelial cells, and its extracellular region, a soluble form of APP770 (sAPP770, also called nexin-2), is proteolytically cleaved for shedding. Abundant sAPP770 is also released from activated platelets. In this study, we used peripheral blood samples from patients with CAD and control subjects and evaluated sAPP770 as a specific biomarker for platelet activation. First, the plasma levels of sAPP770 correlated well with those of the soluble form CD40 ligand (CD40L), an established biomarker for platelet activation. Additionally, flow cytometry analysis using peripheral blood cells showed that CD40L expression is upregulated in activated T cells, while APP770 expression is negligible in all blood cell types except platelets. Following stimulation with collagen or ADP, aggregating platelets immediately released sAPP770. Finally, patients with dual antiplatelet therapy showed significantly lower levels of plasma sAPP770 than those with no therapy. Taken together, our data show that plasma sAPP770 could be a promising biomarker for platelet activation.

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The amyloid precursor protein of Alzheimer's disease is released by human platelets.

Cited by 310 publications

References 47 publications

BACE-1 is expressed in the blood–brain barrier endothelium and is upregulated in a murine model of Alzheimer’s disease

BACE-1 is expressed in the blood–brain barrier endothelium and is upregulated in a murine model of Alzheimer’s disease

Monoamine Oxidase as a Potential Biomarker of the Efficacy of Treatment of Mental Disorders

Amyloid precursor protein 770 is specifically expressed and released from platelets

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