Induction of cerebral β-amyloidosis: Intracerebral versus systemic Aβ inoculation

Eisele, Yvonne S.; Bolmont, Tristan; Heikenwälder, Mathias; Langer, Franziska; Jacobson, Laura H.; Yan, Zheng-Xin; Roth, Klaus Edgar; Aguzzi, Adriano; Staufenbiel, Matthias; Walker, Lary C.; Jucker, Mathias

doi:10.1073/pnas.0903200106

Cited by 259 publications

(275 citation statements)

References 44 publications

(66 reference statements)

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“…Recently, it has been shown that inoculation of brain homogenates from aged Tg(APP23) mice into the brains of young Tg(APP23) mice resulted in the accelerated induction of Aβ deposition in proximity to the inoculation site (24,25). We asked whether this accelerated Aβ deposition also coincided with an increase in GFAP levels that could be monitored using our bigenic Tg(APP23:Gfap-luc) mice.…”

Section: Bli Of Accelerated Disease In Tg(app23:gfap-luc) Mice Inoculmentioning

confidence: 99%

Bioluminescence imaging of Aβ deposition in bigenic mouse models of Alzheimer's disease

Watts

Giles

Grillo

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

105

109

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The undersigned authors wish to note, "The KefFC system of E. coli is maintained in an inactive state by the binding of glutathione (GSH) and is activated by the formation of GSH adducts (GSX), particularly those with bulky substituents. We described two crystal structures with density present in the ligand-binding domain that we interpreted as GSH and GSX. Recently, an independent, experienced crystallographer, who had viewed the structures from our study in a different context, made representations to us that cast doubt on position of the succinimido ring of GSX. We have further reviewed the density maps with the aid of an experienced crystallographer. As a consequence, we believe it is important to draw this altered interpretation of the crystal structures to the attention of readers. In both structures, the density for the backbone of GSH is clear and allows unequivocal assignment of the position of the tripeptide. In PDB coordinate set 3L9X, the density for the succinimido ring is very weak, making interpretation very speculative and the assignment rests on the identity of the ligand added to the crystallization mixture, for which there are two diastereomers in the solutiona possibility that provides some basis for weakening the density. However, in 3L9W there are two anomalies that affect the interpretation of the bound ligand. First, there is no density for the carbon atom attached to the sulfur of GSH and second, there is extra density adjacent to the position of sulfur that could be modelled as a constrained succinimido ring. However, this density could also be water or any other molecule that is trapped in the structure. Thus, while there is good evidence for the peptide, the evidence that it is in the GSH form is uncertain."There are no new data on either the structures or on the gating mechanism. However, we believe that we should be cautious in interpreting the structural data and that the field in general should be made aware of the alternative views of the electron density data. Note that the mutagenesis and spectroscopic data that were presented in the original manuscript are not affected by this alternative interpretation." Tarmo P. The authors note that the following grant should be added to the Acknowledgments: "NIH Grant AG002132." The authors note "The method used for exogenous expression of Ca V 1.2 channels in ref. 32 was incorrectly described as 'viral transduction' in the text. In fact, Yang et al. created transgenic mice with inducible, cardiomyocyte-specific expression of exogenous Ca V 1.2 channels regulated by a tetracycline-inducible promoter. When crossed with a transgenic mouse line expressing doxycycline-regulated reverse transcriptional activator under control of the α-myosin heavy chain protomer, the resulting double transgenic offspring expressed exogenous Ca V 1.2 channels in their cardiac myocytes after treatment with doxycycline. The authors regret the error in describing these methods."www.pnas.org/cgi

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Section: Bli Of Accelerated Disease In Tg(app23:gfap-luc) Mice Inoculmentioning

confidence: 99%

Bioluminescence imaging of Aβ deposition in bigenic mouse models of Alzheimer's disease

Watts

Giles

Grillo

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

105

109

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“…Similarly, i.p. injections of brain extracts laden with Aβ aggregates into transgenic mice expressing the amyloid precursor protein also induced cerebral β-amyloidosis (49,50). Overall, our experience has been that using transgenic mice in exogenous seeding experiments greatly enhances the probability of transmitting pathogenic protein aggregation.…”

Section: Discussionmentioning

confidence: 77%

Intramuscular injection of α-synuclein induces CNS α-synuclein pathology and a rapid-onset motor phenotype in transgenic mice

Sacino¹,

Brooks²,

Thomas³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

289

343

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It has been hypothesized that α-synuclein (αS) misfolding may begin in peripheral nerves and spread to the central nervous system (CNS), leading to Parkinson disease and related disorders. Although recent data suggest that αS pathology can spread within the mouse brain, there is no direct evidence for spread of disease from a peripheral site. In the present study, we show that hind limb intramuscular (IM) injection of αS can induce pathology in the CNS in the human Ala53Thr (M83) and wild-type (M20) αS transgenic (Tg) mouse models. Within 2-3 mo after IM injection in αS homozygous M83 Tg mice and 3-4 mo for hemizygous M83 Tg mice, these animals developed a rapid, synchronized, and predictable induction of widespread CNS αS inclusion pathology, accompanied by astrogliosis, microgliosis, and debilitating motor impairments. In M20 Tg mice, starting at 4 mo after IM injection, we observed αS inclusion pathology in the spinal cord, but motor function remained intact. Transection of the sciatic nerve in the M83 Tg mice significantly delayed the appearance of CNS pathology and motor symptoms, demonstrating the involvement of retrograde transport in inducing αS CNS inclusion pathology. Outside of scrapie-mediated prion disease, to our knowledge, this findiing is the first evidence that an entire neurodegenerative proteinopathy associated with a robust, lethal motor phenotype can be initiated by peripheral inoculation with a pathogenic protein. Furthermore, this facile, synchronized rapid-onset model of α-synucleinopathy will be highly valuable in testing disease-modifying therapies and dissecting the mechanism(s) that drive αS-induced neurodegeneration.amyloid | Parkinson disease S ynucleinopathies are a group of diseases defined by the presence of amyloidogenic α-synuclein (αS) inclusions that can occur in neurons and glia of the central nervous system (CNS) (1-4). In Parkinson disease (PD), a causative role for αS has been established via the discovery of mutations in the αS gene SNCA resulting in autosomal-dominant PD (4-11). Although αS inclusions (e.g., Lewy bodies) are the hallmark pathology of PD, how they contribute to disease pathogenesis remains controversial (1,3,4,12).Postmortem studies have suggested that αS pathology may spread following neuroanatomical tracts (13-15) and between cells (16-18). αS pathology has also been found in the peripheral nervous system (PNS): for example, in the enteric and pelvic plexus (19,20). And it has been suggested that αS pathology might originate in the nerves of the PNS and spread to the CNS (14). Experimentally, it has been reported that intracerebral injections of preformed amyloidogenic αS fibrils in nontransgenic (nTg) and αS transgenic (Tg) mice induce the formation of intracellular αS inclusions that appear to progress from the site of injection (21-26). Collectively, these studies support the notion that αS inclusion pathology may propagate via a prion-like conformational self-templating mechanism (27, 28). A caveat of the direct intracerebral injection of αS is tha...

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“…The ability of Ab and Tau to induce aggregation of endogenous proteins after intracerebral injections may suggest that a-syn could also display seeding capacity in vivo, even if this property has yet to be properly demonstrated. Finally, in contrast to oral, intravenous, intraocular, and intranasal inoculation of Ab-containing brain extracts, which do not lead to any detectable cerebral amyloidosis, 87 intraperitoneal injections of these extracts are able to induce Ab deposition in the brains of young transgenic APP mice after a 7-month incubation period. 88 These results suggest that transport of Ab from periphery to brain can occur and might be a first step in questioning the presumed noninfectious features of AD.…”

Section: Intercellular Transfer Of A-syn In Animal Modelsmentioning

confidence: 99%

A deadly spread: cellular mechanisms of α-synuclein transfer

2011

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Classically, Parkinson's disease (PD) is linked to dopamine neuron death in the substantia nigra pars compacta. Intracytoplasmic protein inclusions named Lewy bodies, and corresponding Lewy neurites found in neuronal processes, are also key features of the degenerative process in the substantia nigra. The molecular mechanisms by which substantia nigra dopamine neurons die and whether the Lewy pathology is directly involved in the cell death pathway are open questions. More recently, it has become apparent that Lewy pathology gradually involves greater parts of the PD brain and is widespread in late stages. In this review, we first discuss the role of misfolded a-synuclein protein, which is the main constituent of Lewy bodies, in the pathogenesis of PD. We then describe recent evidence that a-synuclein might transfer between cells in PD brains. We discuss in detail the possible molecular mechanisms underlying the proposed propagation and the likely consequences for cells that take up a-synuclein. Finally, we focus on aspects of the pathogenic process that could be targeted with new pharmaceutical therapies or used to develop biomarkers for early PD detection. Multiple hypotheses exist to help explain dopamine neuron cell death and Lewy body formation observed in Parkinson's disease (PD). Mutations of the main proteinaceous constituent of Lewy bodies, a-synuclein (a-syn), lead to dominant, familial disease forms. [1][2][3][4][5] More recently, genome-wide association studies (GWASs) identified variants of the a-synuclein gene (SNCA) gene, encoding a-syn protein, that are coupled to increased PD susceptibility, thus clearly linking this protein to idiopathic PD. 6-8 Furthermore, overexpressed and/or misfolded a-syn is pathogenic to cells while a-syn can be secreted from cells, enter other cells, and seed small intracellular aggregates, demonstrating a connection between a-syn and pathogenic mechanisms of PD. [9][10][11][12][13][14][15][16] In parallel, a much-discussed hypothesis by Braak and colleagues 17 states that a pathogenic agent, introduced via ingestion and/or inhalation, may transfer from the entry site along known long, unmyelinated axons to basal brain areas and eventually to brain stem and cortical regions. Although a-syn is unlikely to be this initial pathogen, it might be the initial target of the unknown agent. If a-syn is misfolded because of the action of the unknown agent, it might contribute to the spreading of pathology by moving from one cell to another and triggering misfolding in the recipient cells. If so, it might explain the surprising presence of Lewy bodies in the young neural grafts of transplanted PD patients observed more than a decade after surgery. [18][19][20][21] In this review, we discuss possible mechanisms by which a-syn could spread between cells and have deadly consequences by describing the molecular evidence for a-syn cellular exit, transit to other cells, uptake by cells, intracellular aggregation, and responses to a-syn accumulation.The Relationship Between a-Syn and PD ...

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Induction of cerebral β-amyloidosis: Intracerebral versus systemic Aβ inoculation

Cited by 259 publications

References 44 publications

Bioluminescence imaging of Aβ deposition in bigenic mouse models of Alzheimer's disease

Bioluminescence imaging of Aβ deposition in bigenic mouse models of Alzheimer's disease

Intramuscular injection of α-synuclein induces CNS α-synuclein pathology and a rapid-onset motor phenotype in transgenic mice

A deadly spread: cellular mechanisms of α-synuclein transfer

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