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Widespread dietary exposure of the population of Britain to bovine spongiform encephalopathy (BSE) prions in the 1980s and 1990s led to the emergence of variant Creutzfeldt-Jakob Disease (vCJD) in humans. Two previous appendectomy sample surveys (Appendix-1 and -2) estimated the prevalence of abnormal prion protein (PrP) in the British population exposed to BSE to be 237 per million and 493 per million, respectively. The Appendix-3 survey was recommended to measure the prevalence of abnormal PrP in population groups thought to have been unexposed to BSE. Immunohistochemistry for abnormal PrP was performed on 29,516 samples from appendices removed between 1962 and 1979 from persons born between 1891 through 1965, and from those born after 1996 that had been operated on from 2000 through 2014. Seven appendices were positive for abnormal PrP, of which two were from the pre-BSE-exposure era and five from the post BSE-exposure period. None of the seven positive samples were from appendices removed before 1977, or in patients born after 2000 and none came from individuals diagnosed with vCJD. There was no statistical difference in the prevalence of abnormal PrP across birth and exposure cohorts. Two interpretations are possible. Either there is a low background prevalence of abnormal PrP in human lymphoid tissues that may not progress to vCJD. Alternatively, all positive specimens are attributable to BSE exposure, a finding that would necessitate human exposure having begun in the late 1970s and continuing through the late 1990s. Electronic supplementary material The online version of this article (10.1007/s00401-020-02153-7) contains supplementary material, which is available to authorized users.

Pericytes put the squeeze on cognition Like a computer, the brain needs a reliable source of power, which is provided as oxygen and glucose in the blood. However, in many neurological disorders this energy supply is disrupted. Brain blood flow is controlled by adjustment of the diameters of the vessels supplying the blood. Nortley et al. found that, both in humans developing Alzheimer's disease (AD) and in a mouse model of AD, brain capillaries become squeezed by pericytes (see the Perspective by Liesz). By defining the underlying mechanism, they suggest potential targets for therapy in early AD. Science , this issue p. eaav9518 ; see also p. 223

Vascular compromise occurs early in Alzheimer’s disease (AD) and other dementias1–3. Amyloid β (Aβ) reduces cerebral blood flow4–6 and, as most of the cerebral vasculature resistance is in capillaries7, Aβ might mainly act on contractile pericytes on capillary walls8–10. Employing human tissue to establish disease-relevance, and rodent experiments to define mechanism, we now show that Aβ constricts brain capillaries at pericyte locations in human subjects with cognitive decline. Applying soluble Aβ1-42 oligomers to live human cortical tissue constricted capillaries. Using rat cortical slices, this was shown to reflect Aβ evoking capillary pericyte contraction, with an EC50 of 4.7 nM, via the generation of reactive oxygen species and activation of endothelin ET-A receptors. In freshly-fixed diagnostic biopsies from human patients investigated for cognitive decline, mean capillary diameters were less in subjects showing Aβ deposition than in subjects without Aβ deposition. For patients with Aβ deposition, the capillary diameter was 31% less at pericyte somata than away from somata, predicting a halving of blood flow. Constriction of capillaries by Aβ will contribute to the energy lack1–3 occurring in AD, which promotes further Aβ generation11,12. This mechanism reconciles the amyloid hypothesis13–15 with the earliest events in AD being vascular1.

More than two hundred individuals developed Creutzfeldt-Jakob disease (CJD) worldwide as a result of treatment, typically in childhood, with human cadaveric pituitary-derived growth hormone contaminated with prions. Although such treatment ceased in 1985, iatrogenic CJD (iCJD) continues to emerge because of the prolonged incubation periods seen in human prion infections. Unexpectedly, in an autopsy study of eight individuals with iCJD, aged 36-51 years, in four we found moderate to severe grey matter and vascular amyloid-β (Aβ) pathology. The Aβ deposition in the grey matter was typical of that seen in Alzheimer's disease and Aβ in the blood vessel walls was characteristic of cerebral amyloid angiopathy and did not co-localize with prion protein deposition. None of these patients had pathogenic mutations, APOE ε4 or other high-risk alleles associated with early-onset Alzheimer's disease. Examination of a series of 116 patients with other prion diseases from a prospective observational cohort study showed minimal or no Aβ pathology in cases of similar age range, or a decade older, without APOE ε4 risk alleles. We also analysed pituitary glands from individuals with Aβ pathology and found marked Aβ deposition in multiple cases. Experimental seeding of Aβ pathology has been previously demonstrated in primates and transgenic mice by central nervous system or peripheral inoculation with Alzheimer's disease brain homogenate. The marked deposition of parenchymal and vascular Aβ in these relatively young patients with iCJD, in contrast with other prion disease patients and population controls, is consistent with iatrogenic transmission of Aβ pathology in addition to CJD and suggests that healthy exposed individuals may also be at risk of iatrogenic Alzheimer's disease and cerebral amyloid angiopathy. These findings should also prompt investigation of whether other known iatrogenic routes of prion transmission may also be relevant to Aβ and other proteopathic seeds associated with neurodegenerative and other human diseases.

Targeted cell- or region-specific gene recombination is widely used in the functional analysis of genes implicated in development and disease. In the brain, targeted gene recombination has become a mainstream approach to study neurodegeneration or tumorigenesis. The use of the Cre-loxP system to study tumorigenesis in the adult central nervous system (CNS) can be limited, when the promoter (such as GFAP) is also transiently expressed during development, which can result in the recombination of progenies of different lineages. Engineering of transgenic mice expressing Cre recombinase fused to a mutant of the human oestrogen receptor (ER) allows the circumvention of transient developmental Cre expression by inducing recombination in the adult organism. The recombination of loxP sequences occurs only in the presence of tamoxifen. Systemic administration of tamoxifen can, however, exhibit toxicity and might also recombine unwanted cell populations if the promoter driving Cre expression is active at the time of tamoxifen administration. Here, we report that a single site-specific injection of an active derivative of tamoxifen successfully activates Cre recombinase and selectively recombines tumour suppressor genes in neural progenitor cells of the subventricular zone in mice, and we demonstrate its application in a model for the generation of intrinsic brain tumours., Summary: An active tamoxifen derivative can be used for the in vivo induction of recombination in situ in mice by CreERT2. We show how this method can be used to generate brain tumours through recombination of tumour suppressor genes in the subventricular zone.

Brain tumors are thought to originate from stem/progenitor cell populations that acquire specific genetic mutations. Although current preclinical models have relevance to human pathogenesis, most do not recapitulate the histogenesis of the human disease. Recently, a large series of human gliomas and medulloblastomas were analyzed for genetic signatures of prognosis and therapeutic response. Using a mouse model system that generates three distinct types of intrinsic brain tumors, we correlated RNA and protein expression levels with human brain tumors. A combination of genetic mutations and cellular environment during tumor propagation defined the incidence and phenotype of intrinsic murine tumors. Importantly, in vitro passage of cancer stem cells uniformly promoted a glial expression profile in culture and in brain tumors. Gene expression profiling revealed that experimental gliomas corresponded to distinct subclasses of human glioblastoma, whereas experimental supratentorial primitive neuroectodermal tumors (sPNET) correspond to atypical teratoid/rhabdoid tumor (AT/RT), a rare childhood tumor. Cancer Res; 73(18); 5834–44. ©2013 AACR.