In‐vitro matured human macrophages express Alzheimer's βA4‐amyloid precursor protein indicating synthesis in microglial cells

Bauer, Joachim; König, Gerhard; Strauss, Sylvia; Jonas, U.; Ganter, Ursula; Weidemann, Andreas; Mönning, Ursula; Masters, Colin L.; Volk, Benedikt; Berger, Thomas; Beyreuther, Konrad

doi:10.1016/0014-5793(91)80508-z

Cited by 56 publications

(23 citation statements)

References 59 publications

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“…Recent studies demonstrate that overexpression of activated MMP-9 by HEK/APP695 cells promotes the release of APP (80). Many types of cells, including macrophages, express this glycosylated type I integral membrane protein (64). Our MS/MS analysis detected only peptides derived from its ectodomain in medium from M9A macrophages; this is consistent with proteolytic shedding of APP.…”

Section: Discussionsupporting

confidence: 68%

“…We selected the ␤ 2 integrin subunit and APP for detailed biochemical characterization because both are transmembrane proteins that have been implicated in human pathology (64,75). ␤ 2 integrin subunit, also termed CD18, is a glycosylated type I membrane protein that is part of a leukocytespecific membrane receptor that is critical for host defense (76).…”

Section: Discussionmentioning

confidence: 99%

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MMP-9 Sheds the β2 Integrin Subunit (CD18) from Macrophages

Vaisar

Kassim

Gomez

et al. 2009

Molecular & Cellular Proteomics

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Activated macrophages are essential effectors of immunity and a rich source of matrix metalloproteinase-9 (MMP-9; gelatinase B). To search for cellular substrates of the enzyme, we subjected wild-type macrophages and macrophages expressing an autoactivating form of pro-MMP-9 (M9A macrophages) to proteomics analysis. Twodimensional liquid chromatography together with tandem mass spectrometry identified 467 proteins in medium conditioned by M9A and/or wild-type macrophages. Subtractive proteomics identified 18 candidate MMP-9 substrates. Biochemical studies confirmed that two transmembrane proteins, ␤ 2 integrin subunit (CD18) and amyloid protein precursor (APP), were enriched in the medium of M9A macrophages. To identify potential cleavage sites, we synthesized an overlapping library of peptides that spanned 60 residues of the ectodomain and transmembrane domain of ␤ 2 integrin. Active MMP-9 cleaved a single peptide, ECVKGPNVAAIVGGT, at residues corresponding to Ala 705 and Ile 706 of the ␤ 2 integrin. Peptides corresponding to this cleavage site were detected by tandem mass spectrometric analysis only in medium from M9A macrophages, strongly supporting the proposal that ␤ 2 integrin is shed by autoactivating MMP-9. Our observations indicate that subtractive proteomics in concert with peptide substrate mapping is a powerful approach for identifying proteolytic substrates and suggest that MMP-9 plays previously unsuspected roles in the regulation and shedding of ␤ 2 integrin.

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Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

MMP-9 Sheds the β2 Integrin Subunit (CD18) from Macrophages

Vaisar

Kassim

Gomez

et al. 2009

Molecular & Cellular Proteomics

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“…These datasuggest that both cell types may have the same relationship with the amyloid, e.g., production, secretion, or phagocytosis. While MPS cells are capable of producing P-APP message (Bauer et al, 1991;Haass et al, 19911, this could not be demonstrated for microglia in situ in AD brain (Scott et al, 1993). Alternatively, in AA and AL amyloidoses, MPS cells uptake and process an amyloidogenic precursor and subsequently secrete amyloid fibrils .…”

Section: Basement Membrane Changes In Thementioning

confidence: 91%

Vascular basement membrane components and the lesions of Alzheimer's disease: Light and electron microscopic analyses

Perlmutter

Myers

Barrón

1994

Microscopy Res & Technique

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Alzheimer's disease (AD) is one of several systemic and cerebral diseases that involve the abnormal deposition of fibrillar proteins called amyloids. All amyloids share conformational and staining characteristics, as well as an association with resident tissue macrophages and two extracellular matrix components [heparan sulfate proteoglycan (HSPG) and amyloid P component]. Vascular, glomerular, and Schwann cell basement membrane pathologies have been documented in many forms of amyloidosis, and often amyloid fibrils fuse to and project from the basement membrane in these diseases. The present report demonstrates the vascular basement membrane (VBM) alterations in AD autopsy samples, and details the methodologies used. Electron microscopy reveals the fusion of amyloid fibrils with the VBM and the alteration of the VBM in the absence of amyloid accumulation. Double-labelling and pre-embed immuno-electron microscopy techniques demonstrate the colocalization of amyloid P component and VBM components with amyloid, and also reveal that amyloid P component is not localized to the cerebral VBM. Finally, a novel correlative light/electron microscopy technique demonstrates the association between amyloid P component and cerebral resident tissue macrophages, the microglia. Taken together, these data suggest that the physicochemical processes of amyloid formation, rather than amyloid deposition, may be responsible for VBM pathology.

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“…Of least probability is that microglia play a direct role in the synthesis of amyloid β protein precursor (AβPP) and deposition of Aβ. Although cultured microglia can secrete Aβ and metabolize AβPP in a manner that might favor Aβ deposition [32,39], microglial AβPP mRNA expression is yet to be demonstrated [358]. Conversely, neurons in vivo and neurons in culture exhibit abundant expression of AβPP [213] and are postulated to be the primary source of brain Aβ.…”

Section: Microgliamentioning

confidence: 99%