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The role of innate and adaptive immunity in neurodegeneration remains controversial Alzheimer's disease (AD), Parkinson's disease (PD), and prion diseases such as Creutzfeldt-Jakob disease attack different parts of the central nervous system (CNS) and elicit distinct symptoms, yet they share many biochemical and neuropathological features. These include the formation of protein aggregates in the affected brain regions and progressive activation of non-neuronal cells in the brain that play crucial roles in immune responses. The activation of immune cells in the CNS (“neuroinflammation”) is prominent in these diseases. However, it remains unclear whether boosting or suppressing the immune system, in the brain or in the periphery, may attenuate neurodegeneration. In the case of extraneural prion infections, genetic or pharmacological ablation of components of the immune system, such as B cells and complement, can prevent disease ( 1 ). However, immunotherapies, which have been successful in treating certain types of cancer, have yet to reverse neurodegeneration in any patients. Therefore, the therapeutic promise of this approach remains debatable.

Key Points Amyloids can be broadly defined as insoluble protein aggregates containing a characteristic highly ordered, β-sheet-rich structural motif. The latter can be identified histologically with dyes such as Congo Red and thioflavin. Some amyloids may have an adaptive physiological function; however, most amyloids are thought to be abnormal and are associated with a range of clinical pathologies including systemic amyloidoses and some neurodegenerative disorders. Alzheimer's disease, the most common neurodegenerative disorder, is currently the focus of some of the most exciting and rapidly progressing research on amyloid therapeutics. Two main approaches are being pursued to deplete cerebral amyloid β (Aβ) levels, the primary component of senile plaques associated with Alzheimer's disease. The first approach involves inhibition of the secretases responsible for Aβ production. The second approach involves mobilization of the immune system to promote Aβ clearance. Aβ is produced from the sequential proteolysis of amyloid precursor protein (APP) by β- and γ-secretase. The development of small-molecule inhibitors for these enzymes or complexes as a therapeutic method of depleting monomeric Aβ from the brain has met with considerable success, as well as several challenges. Most notably, the secretases have other non-APP substrates (for example, γ-secretase cleavage of Notch and β-secretase cleavage of Neuregulin 1) that are important for normal physiology. Enhanced clearance of monomeric Aβ and Aβ aggregates by Aβ immunotherapy has been used successfully to lower cerebral Aβ levels and promote cognitive improvement in murine amyloid models. Initial attempts to actively immunize against Aβ in humans were suspended owing to the development of adverse immune responses in some patients. However, passive immunotherapeutic approaches have progressed to clinical trials, and administration of intravenous immunglobulins may also be effective for lowering Aβ levels in the brain. Increasing evidence implicates specific forms of Aβ (for example, soluble Aβ oligomers and intraneuronal Aβ) in Alzheimer's disease-associated neurotoxicity, raising the intriguing possibility that therapies targeted at these pools of Aβ (for example, conformation-specific antibodies) may be effective in ameliorating cognitive deficits associated with Alzheimer's disease by blocking cell death pathways rather than altering Aβ homeostasis. Prion diseases are the only known amyloidoses that act as genuine infectious diseases, with the possible exception of AA amyloidosis. The unusual properties of prion amyloid have presented significant challenges for therapeutics, as well as some opportunities to explore unique therapeutic modalities. In many cases of acquired prion disease, prions first colonize and replicate in extraneural secondary lymphoid organs before being transmitted to the central nervous system (CNS). Blockade of prion replication at these extraneural sites (for example, by inhibition of lymphotoxin β receptor (LTβR) signalling) is an effective method to prevent the spread of prions from the periphery to the CNS and may be useful for post-exposure prophylaxis against prion infections. Attempts to generate active immune responses against PrP Sc (PrP with abnormal conformation) have had little success owing to immune tolerance of ubiquitously expressed endogenous PrP C (PrP with normal conformation). However, passive immunization with large doses of PrP antibodies isolated from Prnp −/− mice can prevent the spread of prions from the periphery to the CNS upon intraperitoneal inoculation. It has not yet been demonstrated that PrP immunotherapy is effective in slowing the rate of prion disease once it has reached the CNS. However, the development of PrP antibodies that effectively cross the blood–brain barrier may dramatically enhance the efficacy of PrP immunotherapy for the treatment of CNS prion infections. Numerous compounds have been investigated or are being developed for their anti-aggregation properties including various amyloid-binding dyes, anti-malarial compounds, protein X mimetics, β-sheet breakers and scyllo-inositol. These compounds are still in development for the treatment of prion diseases and other neurodegenerative disorders; however, some of these compounds are currently in clinical trials for the treatment of systemic amyloidoses. Several lines of evidence indicate that protein aggregates trigger specific cellular toxicity pathways in the brain, including the resistance of non-neuronal cell types and Prnp −/− neurons to PrP Sc -induced toxicity. Intriguingly, PrP C was recently identified as a receptor for oligomeric Aβ, suggesting that diverse protein aggregates may activate common neurotoxicity pathways, which may have important therapeutic implications for amyloid diseases. Diseases such as Alzheimer's disease and systemic amyloidoses are associated with inappropriate deposition of proteins containing a characteristic highly ordered, β-sheet-rich structural motif. The common structural and pathogenic features of these diverse protein aggregation diseases may offer opportunities to develop overarching therapeutic strategies. A growing number of diseases seem to be associated with inappropriate deposition of protein aggregates. Some of these diseases — such as Alzheimer's disease and systemic amyloidoses — have been recognized for a long time. However, it is now clear that ordered aggregation of pathogenic proteins does not only occur in the extracellular space, but in the cytoplasm and nucleus as well, indicating that many other diseases may also qualify as amyloidoses. The common structural and pathogenic features of these diverse protein aggregation diseases is only now being fully understood, and may provide novel opportunities for overarching therapeutic approaches such as depleting the monomeric precursor protein, inhibiting aggregation, enhancing aggregate clearance or blocking common aggregation-induced cellular toxicity pathways.

The misfolding of the cellular prion protein (PrP C ) causes fatal neurodegenerative diseases. Yet PrP C is highly conserved in mammals, suggesting that it exerts beneficial functions preventing its evolutionary elimination. Ablation of PrP C in mice results in well-defined structural and functional alterations in the peripheral nervous system. Many additional phenotypes were ascribed to the lack of PrP C , but some of these were found to arise from genetic artifacts of the underlying mouse models. Here, we revisit the proposed physiological roles of PrP C in the central and peripheral nervous systems and highlight the need for their critical reassessment using new, rigorously controlled animal models.

Microglia are resident immune cells in the brain and spinal cord. These cells provide immune surveillance and are mobilized in response to disparate diseases and injuries. Although microglial activation is often considered neurotoxic, microglia are essential defenders against many neurodegenerative diseases. It also seems increasingly likely that microglial dysfunction can underlie certain neurological diseases without an obvious immune component.

In this perspective, the authors review new developments that suggest that many diseases share features with prion infections. They also highlight some of the critical open questions in prion biology, including how prions damage their hosts and how hosts attempt to neutralize invading prions. Prion science has been on a rollercoaster for two decades. In the mid 1990s, the specter of mad cow disease (bovine spongiform encephalopathy, BSE) provoked an unprecedented public scare that was first precipitated by the realization that this animal prion disease could be transmitted to humans and then rekindled by the evidence that BSE-infected humans could pass on the infection through blood transfusions. Along with the gradual disappearance of BSE, the interest in prions has waned with the general public, funding agencies and prospective PhD students. In the past few years, however, a bewildering variety of diseases have been found to share features with prion infections, including cell-to-cell transmission. Here we review these developments and summarize those open questions that we currently deem most interesting in prion biology: how do prions damage their hosts, and how do hosts attempt to neutralize invading prions?

The cellular prion protein (PrP) is essential to the long-term maintenance of myelin sheaths in peripheral nerves. PrP activates the adhesion G-protein coupled receptor Adgrg6 on Schwann cells and initiates a pro-myelination cascade of molecular signals. Because Adgrg6 is crucial for peripheral myelin development and regeneration after nerve injury, we investigated the role of PrP in peripheral nerve repair. We performed experimental sciatic nerve crush injuries in co-isogenic wild-type and PrP-deficient mice, and examined peripheral nerve repair processes. Generation of repair Schwann cells, macrophage recruitment and remyelination were similar in PrP-deficient and wild-type mice. We conclude that PrP is dispensable for sciatic nerve de- and remyelination after crush injury. Adgrg6 may sustain its function in peripheral nerve repair independently of its activation by PrP.

Prion diseases are caused by PrP Sc , a self-replicating pathologically misfolded protein that exerts toxicity predominantly in the brain. The administration of PrP Sc causes a robust, reproducible and specific disease manifestation. Here, we have applied a combination of translating ribosome affinity purification and ribosome profiling to identify biologically relevant prion-induced changes during disease progression in a cell-type-specific and genome-wide manner. Terminally diseased mice with severe neurological symptoms showed extensive alterations in astrocytes and microglia. Surprisingly, we detected only minor changes in the translational profiles of neurons. Prion-induced alterations in glia overlapped with those identified in other neurodegenerative diseases, suggesting that similar events occur in a broad spectrum of pathologies. Our results suggest that aberrant translation within glia may suffice to cause severe neurological symptoms and may even be the primary driver of prion disease.

Light-sheet microscopy is an ideal technique for imaging large cleared samples; however, the community is still lacking instruments capable of producing volumetric images of centimeter-sized cleared samples with near-isotropic resolution within minutes. Here, we introduce the mesoscale selective plane-illumination microscopy initiative, an open-hardware project for building and operating a light-sheet microscope that addresses these challenges and is compatible with any type of cleared or expanded sample (www.mesospim.org).

Pericytes regulate the development of organ-specific characteristics of the brain vasculature such as the blood–brain barrier (BBB) and astrocytic end-feet. Whether pericytes are involved in the control of leukocyte trafficking in the adult central nervous system (CNS), a process tightly regulated by CNS vasculature, remains elusive. Using adult pericyte-deficient mice (Pdgfbret/ret ), we show that pericytes limit leukocyte infiltration into the CNS during homeostasis and autoimmune neuroinflammation. The permissiveness of the vasculature toward leukocyte trafficking in Pdgfbret/ret mice inversely correlates with vessel pericyte coverage. Upon induction of experimental autoimmune encephalomyelitis (EAE), pericyte-deficient mice die of severe atypical EAE, which can be reversed with fingolimod, indicating that the mortality is due to the massive influx of immune cells into the brain. Additionally, administration of anti-VCAM-1 and anti–ICAM-1 antibodies reduces leukocyte infiltration and diminishes the severity of atypical EAE symptoms of Pdgfbret/ret mice, indicating that the proinflammatory endothelium due to absence of pericytes facilitates exaggerated neuroinflammation. Furthermore,we showthat the presence of myelin peptide-specific peripheral T cells in Pdgfbret/ret ;2D2tg mice leads to the development of spontaneous neurological symptoms paralleled by the massive influx of leukocytes into the brain. These findings indicate that intrinsic changes within brain vasculature can promote the development of a neuroinflammatory disorder.

Key Points Prion diseases are progressive, transmissible neurodegenerative disorders with an invariably fatal outcome. Prions, the infectious agent of prion diseases, accumulate in the central nervous system, in organs of the secondary lymphoid system and in blood. Examples of prion diseases include bovine spongiform encephalopathy (BSE) in cows, scrapie in sheep and goat, chronic wasting disease in deer and elk, and sporadic and variant Creutzfeldt–Jakob disease in humans. Neuronal cytotoxicity of PrP Sc depends on the expression of PrP C . Evidence indicates that the conversion of PrP C to PrP Sc is deleterious, but the mechanisms of neural degeneration are still unclear. In this article, we describe the role of the immune system in prion diseases and review our current understanding of cellular and molecular mechanisms involved in peripheral prion replication and transport. Several prion diseases are transmitted by peripheral prion uptake (for example, ingestion of prion-contaminated food). After prion uptake, a replication phase occurs in lymphoid tissue before neuroinvasion. In the peripheral regions of the host, the abnormally folded, aggregated PrP Sc , is amplified by cells of the immune system (for example, follicular dendritic cells) in the germinal centres, located in B-cell follicles of the spleen or lymph nodes. Depletion of mature follicular dendritic cells delays the development of prion disease following intraperitoneal inoculation. This could form the basis of a post-exposure prophylactic strategy. Recent findings indicate that chronic inflammation can induce the deposition of prion infectivity in organs previously believed to be prion free. In recent years, significant progress has been made in our understanding of the biology of prions, yet many fundamental questions remain unanswered. Aguzzi and Heikenwalder discuss some of these unanswered questions, focusing on the role of the immune system in prion pathogenesis. The prion, a conformational variant of a host protein, is the infectious particle responsible for transmissible spongiform encephalopathy (TSE), a fatal neurodegenerative disease of humans and animals. The principal target of prion pathology is the brain, yet most TSEs also display prion replication at extra-cerebral locations, including secondary lymphoid organs and sites of chronic inflammation. Despite significant progress in our understanding of this infectious agent, many fundamental questions relating to the nature of the prion, including the mechanism of replication and the molecular events underlying brain damage, remain unanswered. Here we focus on the unresolved issues pertaining to prion pathogenesis, particularly on the role played by the immune system.