Isolation and characterization of macrophages from scrapie-infected mouse brain

Merz, George; Schwenk, Valerie; Schuller‐Levis, Georgia; Gruca, S; Wiśniewski, H. M.

doi:10.1007/bf00691096

Cited by 26 publications

(9 citation statements)

References 18 publications

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“…3 0 , 36, 40. 471 or scrapie [35,SO,551. In regions that are vulnerable to hypoxia such as the inferior olivary nucleus and in sector CA1 of the cortiu artiiiiniiis microglial activation without an astrocytic response most likely followed hypoxic neuronal damage [ I 51 from end-stage cardiac or respiratory failure in both CJD and in controls.…”

Section: Discussionmentioning

confidence: 99%

Reactive microgIia in Creutzfeldt‐Jakob disease

Mühleisen

Gehrmann

Meyermann

1995

Neuropathology Appl Neurobio

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Creutzfeldt-Jakob disease (CJD) is characterized by a loss of neurons accompanied by astrogliosis and spongiform changes in the neuropil. It has been recognized that reactive microglia occur in CJD but little is known about the regional distribution and extent of the microglial activation. We have, therefore, examined six brains from cases of sporadic CJD by immunohistochemical labelling of grey and white matter microglia from frontal, parietal, temporal, and occipital lobes, striatum, thalamus, cerebellum and brain stem with RCA-1, LCA, CD68, HLA-DR, and HAM56. Microglial activation occurred in the grey matter where astrogliosis and prion protein (PrP) deposits were prominent. Processes of activated microglia surrounded the outer rim of spongy vacuoles. A diffuse microglial response was seen in the white matter that was immunophenotypically different from grey matter. Double-labelling with microglial markers and anti-PrP showed that activated microglia did not contain PrP-immunoreactivity. Therefore a primary role of microglia in PrP processing seems unlikely. Activated microglia may contribute to neuronal damage in CJD due to their cytotoxic potential.

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Section: Discussionmentioning

confidence: 99%

Reactive microgIia in Creutzfeldt‐Jakob disease

Mühleisen

Gehrmann

Meyermann

1995

Neuropathology Appl Neurobio

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“…For short-term culture and RNA analyses, a slightly different cell protocol was adapted to increase microglial yield and viability (12,31). The basic procedure described above was used, with the inclusion of 0.25% trypsin in the collagenase solution.…”

Section: Methodsmentioning

confidence: 99%

Microglia from Creutzfeldt-Jakob Disease-Infected Brains Are Infectious and Show Specific mRNA Activation Profiles

Baker

Martín

Manuelidis

2002

J Virol

113

100

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Neurons are often assumed to be the principal sites for replication of the infectious agents causing Creutzfeldt-Jakob disease (CJD), scrapie, and bovine spongiform encephalopathy because they express high levels of normal and pathological prion protein (PrP). However, isolated brain cell types have not been evaluated for either infection or gene expression. Microglia purified from CJD-infected mice showed infectivity comparable to that of starting brain homogenate but expressed ϳ50-fold less PrP. CJD-infected microglia also displayed morphological changes indicative of cellular activation. To determine the molecular pathways of activation, we evaluated pertinent transcripts, including those linked to inflammation. Semiquantitative reverse transcription-PCR showed a >4-fold increase in cathepsin S, an enzyme important in antigen presentation, the cytokine interleukin-1␤, and the chemokine B-lymphocyte chemoattractant. The profile of microglial changes induced by the CJD agent differed substantially from activation induced by bacterial lipopolysaccharide or by ␤-amyloid, a structure comparable to pathological PrP. These microglial studies emphasize migratory hematopoietic cells in the dispersion, and possibly replication, of the CJD agent. The low PrP levels in these highly infectious and activated cells further support the concept that pathological PrP is the result of infection rather than the infectious agent itself. Because microglia develop a specific pattern of responses to the CJD agent, microglial markers may be exploited in the diagnosis of these spongiform encephalopathies.Creutzfeldt-Jakob disease (CJD) and scrapie are neurodegenerative diseases caused by infectious agents that are incompletely characterized at the molecular level. The outbreak of bovine spongiform encephalopathy (BSE) and its link to variant CJD in humans makes it important to identify which types of cells carry the agent through the body. Many investigators emphasize neurons in agent spread because these cells accumulate abundant pathological prion protein (PrP), a host protein that aggregates with amyloid properties after infection. Although the contribution of other cell types in the brain, such as microglia, is unknown, such cells are often considered only reactive players. Nevertheless, these infectious agents can be recovered from circulating peripheral white blood cells that have no direct contact with neurons (20).More recent studies have suggested that B lymphocytes or B-cell-dependent follicular dendritic cells are required for infection from the periphery (4, 35). However, this conclusion is contradicted by positive infection in several different B-cellnull mouse models (28, 39). An alternative route for the agent would be through cells of the myeloid lineage (24). Myeloid cells are phenotypically flexible and can develop macrophage or related dendritic cell characteristics in response to environmental stimuli. We have shown that peripheral myeloid cells can carry and maintain the CJD agent for at least 5 weeks in vitro (28...

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“…For RSU 1069 but not PIMO the macrophages in the liver (Kupffer cells), spleen and skin (tissue histiocytes) were associated with high grain density, indicative of the accumulation within these cells of a labelled metabolite and there was a high grain count over small cells in the brain which had a scattered distribution similar to that of microglia (macrophage lineage) (Merz et al, 1987).…”

Section: Tissue Distribution Studiesmentioning

confidence: 96%

Distribution of pimonidazole and RSU 1069 in tumour and normal tissues

Cobb¹,

Nolan²,

Butler³

1990

Br J Cancer

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Summary The tritium-labelled analogues of pimonidazole and RSU 1069 were injected into mice bearing the KHT murine sarcoma which has a hypoxic cell fraction of 1-0%. The distribution of activity at 24 h was recorded using autoradiography and measurement of tissue activity. Autoradiographs with both drugs showed high activity in particular cells within tumour, eye (melanin-associated cells), eyelid (Meibomian gland), liver (centrilobular area), skin (sebaceous gland and melanin), stomach (squamous area), footpad, oesophagus, labial gland, Zymbal's gland, preputial gland, parotid gland (intralobular ducts) and airway epithelium. These tissues had previously been identified as sites of binding of misonidazole. The measurement of total tissue radioactivity showed significantly higher activity in liver, eyelid (Meibomian gland), oesophageal lining, kidney and labial gland than was found in the tumour.Misonidazole (1-(2-nitro-1-imidazolyl)-3-methoxy-2-propanol; MISO) sensitises hypoxic tumour cells to ionising radiation (Asquith et al., 1974). This radiosensitisation is associated with the electron affinity of, MISO and is a fast (subsecond) free-radical process. MISO can also be involved in a separate, slower, enzyme dependent process in which, in the presence of the appropriate reductase(s), the nitro group is reduced yielding cytotoxic species (Varghese et al., 1976;Rauth, 1984). This second process is favoured by a hypoxic environment -such as occurs in parts of many tumoursand this leads to locally enhanced retention. The concept of the preferential retention of reactive bioreduced metabolites in tumours has generated two lines of research. One is directed towards tumour therapy (bioreductive drug therapy). In this, drugs are being developed which, as with MISO, on reduction in the hypoxic milieu of the tumour, form cytotoxic metabolites(s) that bind to critical macromolecules such as DNA. The other line of research is in the field of imaging and spectroscopy.

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Isolation and characterization of macrophages from scrapie-infected mouse brain

Cited by 26 publications

References 18 publications

Reactive microgIia in Creutzfeldt‐Jakob disease

Reactive microgIia in Creutzfeldt‐Jakob disease

Microglia from Creutzfeldt-Jakob Disease-Infected Brains Are Infectious and Show Specific mRNA Activation Profiles

Distribution of pimonidazole and RSU 1069 in tumour and normal tissues

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