Intact Alzheimer amyloid precursor protein (APP) is present in platelet membranes and is encoded by platelet mRNA

Gardella, J.E.; Ghiso, Jorge; Gorgone, G; Marratta, Douglas; Kaplan, Arnold; Frangione, Blas; Gorevic, P. D.

doi:10.1016/s0006-291x(05)80927-1

Cited by 73 publications

(24 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…34 In IFN-␥-primed microglia and macrophages, A␤ has been reported to induce iNOS expression. 20,27,28 Because platelets contain APP in their ␣-granules, [12][13][14][15] we investigated the hypothesis that platelet phagocytosis evokes macrophage activation via proteolytic processing of platelet-derived APP, similar to APP processing in microglia in brain tissue. First, we showed that the mRNA of BACE, an APP-cleaving enzyme, 24 is expressed in human atherosclerotic plaques and macrophages.…”

Section: Discussionmentioning

confidence: 99%

“…[7][8][9][10] Moreover, in human (sub)occluded saphenous vein grafts, the formation of toxic foam cells within mural thrombi is presumably the result of platelet phagocytosis by macrophages. 11 Therefore, we questioned whether in human atherosclerotic plaques platelet phagocytosis evokes macrophage activation and whether proteolytic processing of amyloid precursor protein (APP), present in platelet ␣-granules, [12][13][14][15] is involved in this process.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Platelet Phagocytosis and Processing of β-Amyloid Precursor Protein as a Mechanism of Macrophage Activation in Atherosclerosis

Meyer

Cleen

Cooper

et al. 2002

Circulation Research

134

102

View full text Add to dashboard Cite

Abstract-In human occluded saphenous vein grafts, we previously demonstrated cytotoxic foam cells, presumably derived from macrophages engulfing platelets. In the present study, we investigated whether platelet phagocytosis occurs in human atherosclerotic plaques, whether this activates macrophages, and whether the platelet constituent, amyloid precursor protein (APP), was involved. Immunohistochemistry documented the presence of APP, ␤-amyloid peptide (A␤, cleaved from APP), and platelets (CD9), along with inducible NO synthase (iNOS) and cyclooxygenase-2, two markers of macrophage activation, around microvessels in advanced human carotid artery plaques (nϭ18). A␤ colocalized with iNOS-expressing macrophages that were often surrounded by platelets. In vitro, murine J774 and human THP-1 macrophages were incubated with or without washed human platelets. Coincubation of macrophages and platelets led to platelet phagocytosis (electron and confocal microscopy) and formation of lipid-, APP-, and A␤-containing foam cells. These expressed iNOS mRNA (reverse transcription-polymerase chain reaction) and protein and produced nitrite and tumor necrosis factor-␣ (ELISA). Macrophage pretreatment with 4-(2-aminoethyl)benzenesulfonyl fluoride, a protease inhibitor, reduced APP processing and inhibited NO biosynthesis induced by platelet phagocytosis but not by lipopolysaccharides. Human atherosclerotic plaques and J774 and THP-1 macrophages contained mRNA of the APP-cleaving enzyme ␤-secretase. This is the first demonstration of A␤, a peptide extensively studied in Alzheimer's disease, in human atherosclerotic plaques. It was present in activated iNOSexpressing perivascular macrophages that had phagocytized platelets. In vitro studies indicate that platelet phagocytosis leads to macrophage activation and suggest that platelet-derived APP is proteolytically processed to A␤, resulting in iNOS induction. This represents a novel mechanism for macrophage activation in atherosclerosis. T he composition of an atherosclerotic plaque is an important determinant of plaque stability. Unstable ruptureprone plaques are characterized by a thin fibrous cap that contains few smooth muscle cells. 1,2 Several lines of evidence suggest that macrophage activation in the vulnerable shoulder of the plaque could contribute to plaque rupture. 3,4 We have previously postulated the release of factors toxic to smooth muscle cells, possibly NO, from activated macrophages in human atherosclerotic plaques. 5,6 It has been reported that foam cell formation can be induced by platelet phagocytosis. 7-10 Moreover, in human (sub)occluded saphenous vein grafts, the formation of toxic foam cells within mural thrombi is presumably the result of platelet phagocytosis by macrophages. 11 Therefore, we questioned whether in human atherosclerotic plaques platelet phagocytosis evokes macrophage activation and whether proteolytic processing of amyloid precursor protein (APP), present in platelet ␣-granules, 12-15 is involved in this process.To test this hypothesis, we fi...

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Platelet Phagocytosis and Processing of β-Amyloid Precursor Protein as a Mechanism of Macrophage Activation in Atherosclerosis

Meyer

Cleen

Cooper

et al. 2002

Circulation Research

134

102

View full text Add to dashboard Cite

show abstract

“…An important stage in the formation of more mature deposits is the incorporation of p/A4 into amyloid [10]. This process appears to require a particular segment of the APP molecule to be present [ 18], and to be dependent on the local pH environment [19]. Relatively few diffuse deposits appear to be converted into mature amyloid deposits in the non-CA cases.…”

Section: Discussionmentioning

confidence: 99%

The Ratio of Diffuse to Mature Beta/ A4 Deposits in Alzheimer's Disease Varies in Cases with and without Pronounced Congophilic Angiopathy

Armstrong

Myers²,

Smith³

1993

Dement Geriatr Cogn Disord

View full text Add to dashboard Cite

The density of diffuse, primitive, classic and compact Β/A4 deposits was estimated in the cortex and hippocampus in Alzheimer's disease (AD) cases with and without pronounced congophilic angiopathy (CA). The total density of Β/A4 deposits in a given brain region was similar in cases with and without CA. Significantly fewer diffuse deposits and more primitive/classic deposits were found in the cases with CA. The densities of the primitive, classic and compact deposits were positively correlated in the cases without CA. However, no correlations were observed between the density of the mature subtypes and the diffuse deposits in these cases. In the cases with CA, the density of the primitive deposits was positively correlated with the diffuse but not with the classic deposits. The data suggest that the mature Β/A4 deposits are derived from the diffuse deposits and that the presence of pronounced CA enhances their formation.

show abstract

“…Intact APP is present on the platelet plasma membrane, and is encoded by platelet mRNA [39]. In fact platelet APP is synthesized by the platelet precursor, the megakaryocyte, in the bone marrow, rather than being the result of platelet uptake of circulating APP [16].…”

Section: Introductionmentioning

confidence: 99%

Alzheimer disease and platelets: how’s that relevant

2012

View full text Add to dashboard Cite

Alzheimer Disease (AD) is the most common neurodegenerative disorder worldwide, and account for 60% to 70% of all cases of progressive cognitive impairment in elderly patients. At the microscopic level distinctive features of AD are neurons and synapses degeneration, together with extensive amounts of senile plaques and neurofibrillars tangles. The degenerative process probably starts 20–30 years before the clinical onset of the disease. Senile plaques are composed of a central core of amyloid β peptide, Aβ, derived from the metabolism of the larger amyloid precursor protein, APP, which is expressed not only in the brain, but even in non neuronal tissues. More than 30 years ago, some studies reported that human platelets express APP and all the enzymatic activities necessary to process this protein through the same pathways described in the brain. Since then a large number of evidence has been accumulated to suggest that platelets may be a good peripheral model to study the metabolism of APP, and the pathophysiology of the onset of AD. In this review, we will summarize the current knowledge on the involvement of platelets in Alzheimer Disease. Although platelets are generally accepted as a suitable model for AD, the current scientific interest on this model is very high, because many concepts still remain debated and controversial. At the same time, however, these still unsolved divergences mirror a difficulty to establish constant parameters to better defined the role of platelets in AD.

show abstract

Intact Alzheimer amyloid precursor protein (APP) is present in platelet membranes and is encoded by platelet mRNA

Cited by 73 publications

References 29 publications

Platelet Phagocytosis and Processing of β-Amyloid Precursor Protein as a Mechanism of Macrophage Activation in Atherosclerosis

Platelet Phagocytosis and Processing of β-Amyloid Precursor Protein as a Mechanism of Macrophage Activation in Atherosclerosis

The Ratio of Diffuse to Mature Beta/ A4 Deposits in Alzheimer's Disease Varies in Cases with and without Pronounced Congophilic Angiopathy

Alzheimer disease and platelets: how’s that relevant

Contact Info

Product

Resources

About