Marked increase of neuronal prion protein immunoreactivity in Alzheimer's disease and human prion diseases

Voigtländer, Till; Klöppel, Stefan; Birner, Peter; Jarius, Christa; Flicker, Helga; Verghese-Nikolakaki, S.; Sklaviadis, Theodoros; Guentchev, Marin; Budka, Herbert

doi:10.1007/s004010100405

Cited by 71 publications

(39 citation statements)

References 31 publications

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“…A number of neuropathological, epidemiological, and experimental data suggest a potential interrelationship between AD and prion diseases. The increased immunoreactivity for PrP on neurons and in amyloid plaques observed in brains from AD patients has previously been discussed as a cellular response to oxidative stress (Voigtlander et al, 2001). Vice versa, the occasional co-existence of AD and prion pathology in CJD patients was attributed to a mere timely coincidence because both diseases affect primarily the aging population (Hainfellner et al, 1998).…”

Section: Discussionmentioning

confidence: 97%

Prion infection of mice transgenic for human APP_Swe: increased accumulation of cortical formic acid extractable Aβ(1–42) and rapid scrapie disease development

Baier

Apelt

Riemer

et al. 2008

Intl J of Devlp Neuroscience

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Neuropathological, epidemiological and experimental data indicate a potential interrelationship between Alzheimer's disease and prion diseases. Proteolytic processing of amyloid precursor protein (APP) by beta-secretase was recently suggested to be controlled by prion protein expression. Here, we characterized the prion infection of Tg2576 mice, which overexpress the human APP(Swe) protein. Prion infection of Tg2576-mice led to an early death of the animals, which was preceded by a relatively short symptomatic stage. However, disease-associated gliosis and deposition of misfolded prion protein PrP(Sc) were identical in infected Tg2576-mice and non-transgenic littermate controls. To analyze the effect of prion infection on APP processing and generation of beta-amyloid we determined cortical levels of SDS- and formic acid (FA)-extractable forms of beta-amyloid (1-40) and (1-42) by ELISA. Formic acid-extractable Abeta (1-42) levels were 10-fold higher in infected versus uninfected Tg2576 mice whereas other forms of Abeta were essentially unaffected by the prion infection. Hence, the experimental model demonstrates that a prion infection of the CNS promotes selectively formation of FA-extractable Abeta(1-42) in Tg2576 mice.

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Section: Discussionmentioning

confidence: 97%

Prion infection of mice transgenic for human APP_Swe: increased accumulation of cortical formic acid extractable Aβ(1–42) and rapid scrapie disease development

Baier

Apelt

Riemer

et al. 2008

Intl J of Devlp Neuroscience

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“…A monoclonal antibody against PrP (clone 6H4; Prionics, Schlieren, Switzerland) was used at a dilution of 1 : 500 for the immunohistochemical confirmation of the diagnosis of scrapie. The sections for PrP Sc labelling were pretreated as described previously (Voigtländer et al, 2001). Briefly, a three-step protocol, including hydrated autoclaving, incubation in concentrated formic acid and, subsequently, incubation in guanidine isothiocyanate, was used.…”

Section: Histology and Immunohistochemistrymentioning

confidence: 99%

Prominent corticosteroid disturbance in experimental prion disease

Voigtländer¹,

Unterberger²,

Touma³

et al. 2006

Eur J of Neuroscience

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Prion diseases comprise a group of neurodegenerative disorders that invariably lead to death in affected individuals. The most prominent event in these diseases is a rapid and pronounced neuronal loss, although the cause and the precise mechanisms of neuronal cell death have not been identified so far. Recently, it has been suggested that corticosteroids might play a role in the pathogenesis of neurodegenerative disorders in general, as the regulation of these hormones was found to be disturbed in Alzheimer's and Parkinson's disease, as well as in a transgenic mouse model of Alzheimer's disease. To evaluate the possible corticosteroid disturbances in prion diseases, we determined the concentration of corticosterone metabolites in the faeces of scrapie-inoculated mice during the course of the clinical disease. We observed markedly elevated concentrations of the metabolites during the last 5 weeks of the disease, as well as a severe disturbance of circadian periodicity of corticosterone excretion as much as 2 weeks before this elevation. A simultaneous downregulation of cerebral neuronal glucocorticoid receptors was not detectable by immunohistochemistry, indicating that increased corticosteroids can elicit their effects in mouse scrapie freely. The dysregulation of corticosteroid excretion might act as a further cofactor in the pathogenesis of scrapie, for example by preconditioning nerve cells to disease-immanent neurotoxic stimuli, such as oxidative stress, and to apoptosis.

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“…Spongiform areas in TSE tissues are typified by degenerating neurons that appear swollen and are associated with intracellular and extracellular membrane-bounded vacuoles containing accumulations of curled membrane fragments or other granular material [1,5]. The TSEs are known as prion diseases since prion protein (PrP) appears to be the transmissible agent in these encephalopathies, because accumulation of a disease-related conformer of PrP in the brain tissue of affected organisms occurs along with spongiform pathology [26,49,50]. Prion plaques, reminiscent of amyloid plaques observed in Alzheimer's disease (AD), are sometimes seen in the cerebellum ( Fig.…”

Section: Prion Diseasesmentioning

confidence: 99%

“…Spongiform degeneration in human diseases is accompanied by changes in ubiquitination Grey matter of cortex, hippocampus, cerebellum, midbrain, thalamus, brain stem, motor nuclei of spinal cordYesYes Yes[1,2,26,49,50] Kuru Grey matter of cortex, cerebellum, midbrain, thalamus, brain stem, motor nuclei of spinal cord…”

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confidence: 99%

The ubiquitin–proteasome system in spongiform degenerative disorders

Whatley

Chin

2008

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Summary Spongiform degeneration is characterized by vacuolation in nervous tissue accompanied by neuronal death and gliosis. Although spongiform degeneration is a hallmark of prion diseases, this pathology is also present in the brains of patients suffering from Alzheimer's disease, diffuse Lewy body disease, human immunodeficiency virus (HIV) infection, and Canavan's spongiform leukodystrophy. The shared outcome of spongiform degeneration in these diverse diseases suggests that common cellular mechanisms must underlie the processes of spongiform change and neurodegeneration in the central nervous system. Immunohistochemical analysis of brain tissues reveals increased ubiquitin immunoreactivity in and around areas of spongiform change, suggesting the involvement of ubiquitin-proteasome system dysfunction in the pathogenesis of spongiform neurodegeneration. The link between aberrant ubiquitination and spongiform neurodegeneration has been strengthened by the discovery that a null mutation in the E3 ubiquitin-protein ligase mahogunin ring finger-1 (Mgrn1) causes an autosomal recessively inherited form of spongiform neurodegeneration in animals. Recent studies have begun to suggest that abnormal ubiquitination may alter intracellular signaling and cell functions via proteasome-dependent and proteasome-independent mechanisms, leading to spongiform degeneration and neuronal cell death. Further elucidation of the pathogenic pathways involved in spongiform neurodegeneration should facilitate the development of novel rational therapies for treating prion diseases, HIV infection, and other spongiform degenerative disorders.

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Marked increase of neuronal prion protein immunoreactivity in Alzheimer's disease and human prion diseases

Cited by 71 publications

References 31 publications

Prion infection of mice transgenic for human APP_Swe: increased accumulation of cortical formic acid extractable Aβ(1–42) and rapid scrapie disease development

Prion infection of mice transgenic for human APP_Swe: increased accumulation of cortical formic acid extractable Aβ(1–42) and rapid scrapie disease development

Prominent corticosteroid disturbance in experimental prion disease

The ubiquitin–proteasome system in spongiform degenerative disorders

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Marked increase of neuronal prion protein immunoreactivity in Alzheimer's disease and human prion diseases

Cited by 71 publications

References 31 publications

Prion infection of mice transgenic for human APPSwe: increased accumulation of cortical formic acid extractable Aβ(1–42) and rapid scrapie disease development

Prion infection of mice transgenic for human APPSwe: increased accumulation of cortical formic acid extractable Aβ(1–42) and rapid scrapie disease development

Prominent corticosteroid disturbance in experimental prion disease

The ubiquitin–proteasome system in spongiform degenerative disorders

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Prion infection of mice transgenic for human APP_Swe: increased accumulation of cortical formic acid extractable Aβ(1–42) and rapid scrapie disease development

Prion infection of mice transgenic for human APP_Swe: increased accumulation of cortical formic acid extractable Aβ(1–42) and rapid scrapie disease development