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b-Amyloid Prions and the Pathobiologyof Alzheimer’s Disease

Joel C. Watts1 and Stanley B. Prusiner2

1Tanz Centre for Research in Neurodegenerative Diseases and Department of Biochemistry, Universityof Toronto, Toronto, Ontario M5T 2S8, Canada

2Institute for Neurodegenerative Diseases, Departments of Neurology and of Biochemistry and Biophysics,Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, California 94143

Correspondence: [email protected]

Alzheimer’s disease (AD) is the most common neurodegenerative disease in humans and willpose a considerable challenge to healthcare systems in the coming years. Aggregation of theb-amyloid (Ab) peptide within the brain is thought to be an initiating event in AD pathogen-esis. Many recent studies in transgenic mice have provided evidence that Ab aggregatesbecome self-propagating during disease, leading to a cascade of protein aggregation in thebrain, which may underlie the progressive nature of AD. The ability to self-propagate and theexistence of distinct “strains” reveals that Ab aggregates exhibit many properties indistin-guishable from those of prions composed of PrPSc proteins. Here, we review the evidencethat Ab can become a prion during disease and discuss how Ab prions may be important forunderstanding the pathobiology of AD.

Alzheimer’s disease (AD) is the most com-mon cause of dementia in humans and is

most frequently diagnosed in individuals 65 yrof age or older. The incidence of AD varies withage: about one in nine people age 65 or olderwill develop AD, whereas about one in threeindividuals age 85 or older will be diagnosedwith the disease (Hebert et al. 2013). Early-on-set cases of AD, which occur in individualsyounger than age 65, are comparatively rareand include familial cases caused by mutationsin genes linked to the production of the b-am-yloid (Ab) peptide. The predominant clinicalsymptoms of AD are cognitive deficits andbehavioral changes. AD patients typically firstpresent with difficulties in remembering recent

occurrences, but with intact memories of olderevents. The earliest, predementia stages of thedisease are often classified clinically as mild cog-nitive impairment, which describes the pres-ence of memory problems greater than thoseexpected from normal aging. As the disease pro-gresses, additional symptoms become apparent,which may include problems with language,confusion, mood swings, long-term memoryloss, and withdrawal from society. Eventually,AD patients become completely dependent oncaregiver assistance. There are currently nocures or effective treatments for AD. Althoughavailable treatments may temporarily improvebehavioral problems, they do not address theroot cause of the disease or its progression.

Editor: Stanley B. Prusiner

Additional Perspectives on Prion Diseases available at www.perspectivesinmedicine.org

Copyright # 2017 Cold Spring Harbor Laboratory Press; all rights reserved

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AD is a progressive neurodegenerative dis-ease of aging. The brains of AD patients exhibita remarkable loss of synapses and neurons, whichresults in an overall shrinkage of the brain, par-ticularly in the temporal and parietal lobes as wellas in the frontal cortex. At the microscopic level,two principal pathologies are observed: amyloid(senile) plaques and neurofibrillary tangles(NFTs). The dense, extracellular amyloid plaquesare composed of aggregated Ab peptide, whereasthe intracellular NFTs are made up of paired he-lical filaments of hyperphosphorylated tau pro-tein. Ab is generated by the sequential endopro-teolytic cleavage of the amyloid precursorprotein (APP), a Type-1 transmembrane proteinthat exists as three different isoforms with lengths

of 695, 751, and 770 amino acids. In the amyloi-dogenic processing pathway, APP is cleaved bytwo different proteases: b-secretase and g-secre-tase (Fig. 1).b-Secretase first cleaves the extracel-lular juxtamembrane region of APP, resulting ina membrane-embedded fragment termed C99.The transmembrane portion of C99 is thencleaved by g-secretase, a multiprotein complexthat includes the enzymatically active presenilinproteins (De Strooper et al. 2012), freeing theAb peptide. Cleavage of C99 by g-secretase isheterogeneous in nature and results in the gen-eration of Abpeptides varying in length from 37to 43 amino acids (Benilova et al. 2012). If APPis first cleaved bya-secretase instead of b-secre-tase, the generation of Ab is prevented.

721

Aβ

Aβ

γ-Secretase

γ-Secretase

β-Secretase

β-Secretase

sAPPβ

+

+

37–431 770

770

770

APP

CytoplasmExtracellular space

67267118

AICD

C99

Aβ

18

Figure 1. Generation of b-amyloid (Ab) peptide via endoproteolytic cleavage of amyloid precursor protein(APP). The mature form of the longest isoform of human APP (following removal of an N-terminal signalpeptide) spans residues 18–770. In the amyloidogenic pathway, cleavage of the APP extracellular domain by b-secretase produces a secreted fragment termed sAPPb and a membrane-embedded C-terminal fragment calledC99. Cleavage of C99 by g-secretase produces the APP intracellular domain (AICD) and the Ab peptide.Cleavage of APP by g-secretase is heterogeneous, resulting in the generation of Ab peptides that vary in lengthbetween 37 and 43 residues.

J.C. Watts and S.B. Prusiner

2 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a023507

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The amyloid cascade hypothesis, which isthe most widely accepted theory for the molec-ular sequence of events in AD, postulates that theinitiating event in AD is the aggregation andsubsequent deposition of Ab peptide in thebrain (Hardy and Selkoe 2002). This results inthe hyperphosphorylation and polymerizationof tau into NFTs and, ultimately, degeneration ofneurons. This hypothesis is supported by thefollowing observations: (1) Mutations in thegene encoding APP cause early-onset forms ofAD and increase the production of Ab or en-hance its aggregation potential (Chartier-Harlinet al. 1991; Citron et al. 1992); (2) duplication ofthe APP coding locus results in early-onset AD(Rovelet-Lecrux et al. 2006); (3) in Down’s syn-drome patients, an extra copy of chromosome21, which contains the APP gene, invariablycauses AD-like pathological changes in the brain(Wisniewski et al. 1985); (4) mutations in theAPP gene that decrease Ab production are pro-tective against AD (Jonsson et al. 2012); and (5)mutations in the genes encoding the presenilinproteins increase the relative abundance of pro-amyloidogenic Ab isoforms and cause early-on-set AD (Sherrington et al. 1995). Thus, increasedAb production and deposition in the brain issufficient to cause AD, suggesting that Ab aggre-gation is central to AD pathogenesis. In contrast,mutations in the gene encoding tau result in theproduction of NFTs in the brain (Hutton et al.1998; Spillantini et al. 1998), but not amyloidplaques. Such patients develop a tauopathytermed FTDP-17 that is clinically and patholog-ically distinct from AD, revealing that tau muta-tions are insufficient to elicit the full neuropath-ological spectrum observed in AD.

MOUSE MODELS OF ALZHEIMER’S DISEASE

Transgenic (Tg) mice that overexpress mutanthuman APP containing one or more mutationsthat cause early-onset, familial forms of ADdevelop Ab-containing amyloid plaques withaging (Morrissette et al. 2009). These mice, re-ferred to hereafter as Tg(AD) mice, thus reca-pitulate one of the key neuropathological hall-marks of AD. The kinetics of Ab deposition inTg(AD) mice is governed by the relative level of

APP overexpression as well as the specific mu-tations present. For example, Tg2576 mice ex-pressing human APP containing the Swedishmutation (K670N/M671L) (Citron et al.1992; Mullan et al. 1992), which causes en-hanced cleavage of APP by b-secretase (Haasset al. 1995) and, consequently, increased Abproduction, develop Ab plaques beginning at�12 mo of age (Hsiao et al. 1996). In contrast,TgCRND8 mice expressing a mutant APP allelecontaining the Swedish mutation and the Indi-ana mutation (V717F) (Murrell et al. 1991),which increases the relative abundance of themore aggregation-prone Ab42 isoform (Suzukiet al. 1994), develop amyloid plaques at �3–4 mo of age (Chishti et al. 2001).

Some lines of Tg(AD) mice exhibit age-de-pendent memory impairment, mimicking thecognitive deficits observed in AD patients, andexhibit some tau hyperphosphorylation (for re-view, see Morrissette et al. 2009). Moreover, thecerebrospinal fluid (CSF) of Tg(AD) mice con-tains increased levels of tau and decreased levelsof Ab42 peptide, mirroring the biomarker sig-nature of individuals with AD (Maia et al.2013). These data support the translational util-ity of Tg(AD) mice. Indeed, these animals havebeen used to show that reducing levels of Abaggregates in the brain, either by vaccination orpassive immunotherapy, can rescue cognitivedeficits (Schenk et al. 1999; Bard et al. 2000;Janus et al. 2000). However, current Tg(AD)mice do not constitute an ideal animal modelof AD because, unlike AD patients, Tg(AD)mice do not develop NFTs in response to Abaggregation and do not display frank neuronalloss (Jucker 2010).

Tg(AD) mice do not exhibit overt progres-sive clinical signs of neurological illness withaging, despite the presence of abundant Abplaques. Thus, the only way of assessing thekinetics of Ab deposition in the brain is to per-form postmortem analysis of fixed tissue usingneuropathological techniques. This is not idealfor several reasons. First, this greatly increasesthe number of animals needed for a study, asseparate cohorts are required for each timepoint under investigation. Second, it necessi-tates “guessing” when Ab deposition is expect-

Ab Prions and AD Pathobiology

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ed to occur in the brain. Finally, it hinders thedevelopment of therapeutics because of the lackof easily and rapidly quantifiable measures ofdisease. One solution to this problem is theuse of bioluminescence imaging (BLI) to mon-itor the kinetics of Ab deposition in living mice.Tg mice that express firefly luciferase (luc) un-der the control of the glial fibrillary acidic pro-tein (GFAP) promoter (Zhu et al. 2004) emitincreased levels of light from their brains in re-sponse to stimuli that cause astrocytic gliosisand a concomitant upregulation of GFAP pro-tein in astrocytes. Because GFAP-positive astro-cytes are frequently found around the perime-ters of Ab amyloid deposits in the brain, wehypothesized that Tg(Gfap-luc) mice would beuseful for tracking the kinetics of Ab depositionin vivo. Indeed, bigenic mice expressing a mu-tant APP transgene and the Gfap-luc reporter

exhibited age-dependent increases in the brainbioluminescence signal (Fig. 2), providing aquantitative assessment of the kinetics of Abdeposition in living mice (Watts et al. 2011).

Two recently described Tg(AD) models haveprovided significant advances to the field.Knock-in mice in which the mouse APP genewas modified so that it contains a humanizedAb sequence and the Swedish and Iberian(I716F) (Guardia-Laguarta et al. 2010) muta-tions develop typical age-dependent Ab pathol-ogy and memory deficits (Saito et al. 2014).These mice are noteworthy in that APP isexpressed at physiological levels and with cor-rect spatiotemporal patterning. A promisingTg(AD) rat model has also been developed re-cently. TgF344-AD rats, which express humanAPP containing the Swedish mutation and amutant presenilin 1 transgene, develop Ab pa-

30

Intracerebral inoculation of purifiedor synthentic Aβ aggregates

Tg(APP23:Gfap-luc)

Tg(Gfap-luc)

Tg(APP23:Gfap-luc)

25

20

15

10

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hoto

ns/s

ec)

5

00 50 100 150 200

Time from inoculation (days)

250 300 350 400 450 500 550

None

Inoculum

NonePurified Aβ aggregatesSynthetic Aβ aggregates

Recipient line

Figure 2. Monitoring spontaneous and induced Ab deposition in bigenic mice using in vivo bioluminescenceimaging (BLI). The brain BLI signal in bigenic Tg(APP23:Gfap-luc) mice (red) exhibits an age-dependentincrease, which is indicative of cerebral Ab deposition, compared with Tg mice expressing just the Gfap-lucreporter (blue). Intracerebral inoculation of Tg(APP23:Gfap-luc) mice with either Ab aggregates purified fromthe brain of an aged APP23 mouse (black) or Ab aggregates formed from synthetic Ab(1-40) peptide (green)accelerate the onset of the brain BLI signal increase compared with uninoculated mice, indicating that bothinocula contain Ab prions. (This figure has been adapted from Stohr et al. 2012, with permission from theNational Academy of Sciences # 2012.)



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thology and cognitive deficits and some associ-ated tau pathology and neuronal loss (Cohenet al. 2013).

EVIDENCE FOR THE EXISTENCE OF AbPRIONS IN AD

The pioneering work of Gajdusek, Gibbs, andAlpers revealed that Creutzfeldt–Jakob disease(CJD) and kuru could be transmitted to non-human primates, demonstrating for the firsttime that these human spongiform encephalop-athies are transmissible illnesses (Gajdusek et al.1966; Gibbs et al. 1968). It is now known thatprions composed of misfolded and aggregatedprion protein (PrP) are the infectious agent inthese diseases (Colby and Prusiner 2011). PrPprions were originally defined as proteinaceousinfectious particles that cause rare, transmissi-ble neurodegenerative diseases such as scrapieand CJD (Prusiner 1982) but are now moregenerally defined as alternative protein confor-mations that exhibit self-propagation (Prusiner2012). There are two key features of prions: (1)At least two distinct stable conformational statesof the protein exist in the absence of any post-translational modifications, one of which ex-hibits a propensity for forming multimericstructures and/or aggregates; and (2) the multi-meric state is self-propagating, meaning that itcan catalyze the conversion of the “normal,”monomeric conformation into an additionalcopy of the prion conformation.

Evidence that Ab becomes a prion duringAD pathogenesis is growing. In AD patients,the pattern of Ab deposition in the brain isnot random in nature. Instead, Ab depositionfollows a stereotypical progression through fivedistinct phases. Phases 1–3 are associated withAb deposits occurring in nondemented indi-viduals, whereas phases 3–5 are associatedwith AD patients (Thal et al. 2002). In phase 1,Ab deposits are exclusively found in the neocor-tex and then spread to the hippocampus inphase 2. In phase 3, Abdeposits can additionallybe found in the amygdala, thalamus, and stria-tum. In phase 4, certain areas of the brainstemand the substantia nigra become laden with Abdeposits; finally, in phase 5, Ab deposits can also

be found in additional brainstem nuclei andthe cerebellum. This progressive, nonrandomspreading of cerebral Ab deposition is reminis-cent of the spread of PrP prions throughout thebrain by templated conformational conversion.Unlike in AD, amyloid plaques are only presentin the brain in �10% of CJD cases (DeArmondet al. 2004). However, upon purification, PrPprions aggregate to form rod-like structuresthat exhibit all of the properties of amyloid, in-cluding Congo red birefringence (Prusiner et al.1983). The molecular and pathological similar-ities between AD and the PrP prion diseases ledto speculation that prions may feature in thepathogenesis of AD, and that like CJD andkuru, AD may be transmissible to nonhumanprimates (Prusiner 1984).

Attempts to transmit AD to monkeys pro-duced discordant results (Table 1). Gajdusekand colleagues inoculated 52 different cases ofsporadic and familial AD into a variety of pri-mate species and found that only two of thecases transmitted disease (Goudsmit et al.1980). However, the resultant pathology in themonkeys inoculated with these two cases didnot resemble AD; instead, it was identical tothat observed in monkeys inoculated with CJDand kuru. Moreover, new preparations of inoc-ula from these two cases failed to transmit dis-ease, suggesting that contamination or otherlaboratory errors are a more likely explanationfor the initial positive transmissions. Similar is-sues may explain the inability to reproduce aninitial finding that buffy coat fractions from theblood of AD patients induce a spongiform en-cephalopathy in inoculated hamsters (Manueli-dis et al. 1988; Godec et al. 1994).

Later, Ridley, Baker, and colleagues showedthat marmosets inoculated with brain homog-enate from an AD patient develop some Ab-containing senile plaques and cerebral amyloidangiopathy 6–7 yr postinjection (Baker et al.1993, 1994). A total of 24 out of 27 marmosetsinjected with brain homogenate containing Abaggregates exhibited modest numbers of Abdeposits after incubation periods of up to�8 yr (Ridley et al. 2006). All monkeys thatsurvived .3.5 yr postinoculation exhibitedAb deposits. Only five of 29 uninjected mar-



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mosets aged .10 yr and none of the unin-jected marmosets aged 5–10 yr exhibitedspontaneous Ab deposits. These studies alsofound that brain homogenate from non-ADpatients, synthetic Ab aggregates, and CSFfrom AD patients were poor inducers of Abdeposition in marmosets. Importantly, noclinical signs of AD or NFTs were observedin any of the Ab-positive inoculated animals,suggesting that although cerebral b-amyloid-osis can be initiated or accelerated by inocula-tion of preformed Ab aggregates, the full clin-icopathologic spectrum of AD cannot berecapitulated by inoculation, at least withinthe time frame studied.

USING TRANSGENIC MICE TO STUDYAb PRIONS

The most convincing evidence for the existenceof self-propagating Ab aggregates (or, simply,Ab prions) in AD has been shown by in vivoseeding studies in Tg(AD) mice. In many linesof Tg(AD) mice, such as the widely used Tg2576and APP23 (Sturchler-Pierrat et al. 1997) mod-els, spontaneous Ab deposits are not observeduntil the animals are older, providing a windowduring which the induction of Ab deposition byinoculation of exogenous Ab aggregates can beassessed. In a typical in vivo seeding experiment,young (2- to 3-mo-old) Tg mice (that have not

Table 1. Attempts to transmit Alzheimer’s disease to primates

Number of

cases

inoculated Host primate(s)

Incubation period

examined Findings Reference(s)

34 (sporadicAD)

Chimpanzees, capuchins,squirrel monkeys,spider monkeys, Africangreen monkey,stumptail monkeys

13 casesexamined for.50 mo; 21cases examinedfor ,50 mo

No clinical signs ofneurological disease in anyof the inoculated animals;Ab pathology analysis notperformed

Goudsmitet al. 1980

18 (familialAD)

Chimpanzees, capuchins,mangabeys, squirrelmonkeys, spidermonkeys, African greenmonkey, stumptailmonkeys, rhesusmonkeys, cynomolgusmonkeys

4 cases examinedfor .50 mo;14 casesexamined for,50 mo

16/18 cases produced noclinical signs ofneurological disease in theinoculated animals; Abpathology analysis notperformed; 2/18 casesproduced a spongiformencephalopathy at 23–40 mo postinoculationa

Goudsmitet al. 1980

3 (sporadicAD)

Marmosets Up to 95 mo No clinical signs ofneurological disease in anyof the inoculated animals;8/9 inoculated animalsexhibited Ab pathology(plaques and cerebralamyloid angiopathy)

Baker et al.1994; Ridleyet al. 2006

1 (familialAD)

Marmosets Up to 72 mo No clinical signs ofneurological disease in anyof the inoculated animals;4/5 inoculated animalsexhibited Ab pathology(plaques and cerebralamyloid angiopathy)

Ridley et al.2006

aThese two positive transmissions were not reproducible.



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yet developed deposits) are intracerebrally in-jected with brain extract containing abundantAb aggregates, and, subsequently, the inductionof Ab deposition is examined following anincubation period of 3–5 mo. Two inoculationtechniques, stereotaxic and non-stereotaxic(“standard”) injections, have been used tointroduce exogenous Ab aggregates into thebrains of Tg(AD) mice. Stereotaxic inoculationscommonly involve the injection of 2–3 mL ofbrain extract directly into the hippocampusand overlying cortex using a Hamilton syringe.Although this technique is time-consuming, it isadvantageous because Ab aggregates can be in-troduced into highly defined brain regions (Ei-sele et al. 2009). The standard procedure in-volves the inoculation of �30 mL of brainextract into the right cerebral hemisphere usinga standard syringe and a 27-gauge needle (Stohret al. 2012). This technique is less precise(roughly injecting the inoculum into the thala-mus and the overlying hippocampal and corticalregions) but is much more rapid.

In 2000, Lary Walker and colleagues showedthat intracerebral inoculation of brain extractsfrom AD patients into Tg2576 mice inducedsmall amounts of cerebral Ab deposition fol-lowing an incubation period of 5 mo (Kaneet al. 2000). No Ab deposition was observedin mice injected with brain extract from a youngindividual or in age-matched uninjected ani-mals, and only minor amounts of induced Abdeposition were seen in mice inoculated withbrain extract from an aged patient withoutAD. Later, Walker, working with Mathias Juckerand colleagues, revealed that Ab aggregatespresent in the brain extracts were necessary toinduce Ab deposition (Meyer-Luehmann et al.2006). Stereotactic inoculation of APP23 miceinto the hippocampus and overlying cortexwith brain extract from aged Tg(AD) mice re-sulted in the induction of Ab deposition afteran incubation period of 4 mo. The induction ofcerebral Ab deposition could be blocked or sig-nificantly attenuated by either (1) immunode-pleting the brain extracts of Ab aggregatesbefore inoculation, (2) passively immunizingthe mice with anti-Ab antibodies, or (3) treat-ing the brain extract with formic acid before

inoculation. Depletion of Ab aggregates frombrain extracts using a small molecule also sup-pressed seeding activity (Duran-Aniotz et al.2014). These experiments indicated that, likePrP prions, brain-derived Ab aggregates areself-propagating. However, no induced Ab dep-osition was observed in mice inoculated with avariety of synthetic Ab aggregate preparations,implying that not all Ab aggregates are capableof self-propagation (Meyer-Luehmann et al.2006).

Although earlier efforts failed to show anyseeding of cerebral Ab deposition following pe-ripheral or systemic application of Ab seeds(Eisele et al. 2009), examining later time pointsfollowing intraperitoneal inoculation of APP23mice with Tg(AD) brain extract revealed thatcerebral Ab deposition can be initiated by pe-ripheral inoculation, suggesting that Ab prions,like PrP prions, are neuroinvasive (Eisele et al.2010). This is not an artifact of ectopic APPexpression in the periphery owing to the useof the Thy-1 promoter to drive mutant APPexpression in APP23 mice, as cerebral Ab dep-osition can also be induced by peripheral Abinoculation in R1.40 Tg mice, which expressmutant APP under the control of its endoge-nous promoter (Eisele et al. 2014). Similarly,cerebral Ab deposition can also be induced byintracerebral inoculation of R1.40 mice withAb-containing brain extract (Hamaguchi et al.2012), arguing that cerebral Ab induction can-not be explained as an artifact arising from im-proper patterns of APP expression. Although amajority of studies have shown that cerebral Abdeposition can be induced in Tg(AD) mice orrats (Rosen et al. 2012) that express mutant APP,it is also possible to induce Ab deposition in Tgmice that overexpress wild-type human APPand do not develop spontaneous cerebral Abdeposition within their normal lifespan. Intra-cerebral inoculation of HuAPPwt mice with ADpatient brain extract resulted in the induction ofAb pathology at �10 mo postinoculation (Mo-rales et al. 2012). It is not yet known whether Abinduction can be induced in non-Tg mice orrats.

The specific assemblies of Ab responsiblefor inducing cerebral Ab deposition are not cur-



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rently known. Ab aggregates purified from thebrains of Tg(AD) mice are potent inducers ofAb deposition in the brain (Fig. 2) (Stohr et al.2012), suggesting that Ab aggregates themselvesare the infectious prion species. This was con-firmed by demonstrating that Ab aggregatescomposed exclusively of synthetic Ab peptidescan also initiate cerebral Ab deposition inAPP23 mice (Fig. 2) (Stohr et al. 2012, 2014).Treatment of Ab prion preparations with pro-teinase K (PK) did not abolish their infectivity(Langer et al. 2011; Stohr et al. 2012), implyingthat self-propagating Ab aggregates are denselypacked and likely large in size. This is supportedby the observation that formaldehyde treatmentdoes not inactivate Ab prion activity present inbrain extracts (Fritschi et al. 2014a) and theremarkable finding that Ab prions can persistfor up to 6 mo postinoculation in Ab-inoculat-ed APP knockout mice (Ye et al. 2015a). How-ever, soluble Ab species present in Tg(AD) orAD patient brain extracts that are sensitive to PKdigestion can also induce cerebral Ab deposi-tion in APP23 mice (Langer et al. 2011; Fritschiet al. 2014b), suggesting that multiple distinctAb prion strains are capable of exhibiting self-propagation.

Like PrP prions, Ab prions are capable ofinducing cerebral Ab deposition even whenpresent at low levels in the inoculum. For exam-ple, induced Ab deposition was still apparent inTg2576 mice when injected with 105- to 106-fold dilutions of aged Tg2576 brain extract(Morales et al. 2015). Moreover, brain extractsfrom patients with mild cognitive impairmentor nondemented individuals with AD neuropa-thology were also capable of inducing cerebralAb deposition in Tg(AD) mice (Duran-Aniotzet al. 2013). Induced Ab prions also appear to“spread” away from the original site of inocula-tion (Eisele et al. 2009; Ye et al. 2015b), provid-ing a potential molecular explanation for theprogression of Ab pathology observed in ADpatients (Thal et al. 2002).

STRAINS OF Ab PRIONS

In the PrP prion diseases, distinct strains of pri-ons can be classified according to their incuba-

tion periods upon inoculation into rodents, theresultant clinical signs of disease and neuro-pathological features, and their biochemicalcharacteristics, such as their relative resistanceto protease digestion and their stability uponexposure to chemical denaturants (Collingeand Clarke 2007). A myriad of evidence arguesthat prion strain-specific properties are encodedwithin unique conformations of PrP aggregates(Bessen and Marsh 1994; Telling et al. 1996). ADis a clinically and pathologically heterogeneousdisorder, with variability present in the age ofonset, the rate of cognitive decline, and the mor-phology and neuroanatomical location of Abpathology (i.e., parenchymal vs. vascular). It isconceivable that some of this heterogeneity mayarise because of the presence of distinct strainsof Ab prions in the brain.

The first evidence for conformational het-erogeneity of Ab aggregates was observed inAb fibrils generated from synthetic Ab usingeither quiescent or agitated conditions (Petkovaet al. 2005). The two types of fibrils exhibiteddifferent morphologies when examined usingelectron microscopy and solid-state nuclearmagnetic resonance (NMR) spectroscopy.Moreover, the distinct morphologies weremaintained upon serial seeding, indicatingthat these unique structural states are self-prop-agating. Variations in the morphology of fibrilsformed from synthetic Ab have also been ob-tained by varying the buffer conditions and/orthe formation temperature (Meinhardt et al.2009; Kodali et al. 2010). At the molecular level,structural polymorphism may arise as a result ofdifferences in symmetry and the conformationsof Ab residues not involved in the core parallelin-register b-sheet structure (Paravastu et al.2008). Interestingly, Ab fibrils formed fromsynthetic Ab can also exhibit strain-like behav-ior in vivo. Synthetic Ab42 polymerized in thepresence of 0.1% (wt/vol) sodium dodecyl sul-fate (SDS) resulted in shorter fibrils than whenAb42 was aggregated in the absence of SDS(Stohr et al. 2014). When inoculated intoAPP23 mice, Ab42 fibrils generated in the ab-sence of SDS induced a greater number of Abplaques, which contained a higher ratio ofAb42/Ab40 peptides than the plaques in mice



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inoculated with Ab42 fibrils produced in thepresence of SDS.

Distinct strains (or “morphotypes”) of Abprions have also been observed between twodifferent lines of Tg(AD) mice, APP23 andAPPPS1 (Radde et al. 2006). Using luminescentconjugated polymers (Sigurdson et al. 2007), itwas shown that the Ab deposits present in thebrains of the two Tg(AD) lines emit distinctfluorescent spectra, which is suggestive of con-formationally unique aggregates (Heilbronneret al. 2013). When APP23 Ab aggregates wereinoculated into APP23 mice, the induced Abprions were spectrally similar to those presentin aged APP23 mice. In contrast, when APPPS1Ab prions were inoculated into APP23 mice,the induced Ab aggregates produced spectrasimilar to those present in aged APPPS1 mice,indicating that the brain extracts from aged

APP23 and APPPS1 mice contain distinctstrains of self-propagating Ab aggregates.

By mixing synthetic Ab with fibrils isolatedfrom an AD patient sample, it was shown thatthe Ab aggregates present in AD patients arestructurally distinct from those formed sponta-neously from synthetic Ab (Paravastu et al.2009). Using a similar approach, it was recentlydetermined that Ab aggregates isolated fromtwo different sporadic AD patients produceseeded Ab aggregates with unique structuralproperties, arguing that distinct strains of Abaggregates may exist among AD patients (Luet al. 2013). Indeed, the Ab42 aggregates in pa-tients with a more rapidly progressive version ofAD are conformationally distinct from those inAD patients with a stereotypical disease course,as determined by a conformation-dependentimmunoassay (Cohen et al. 2015). The existence

Inoculum:

Inoculum:

Swedish AD

Swedish ADAPP23

APP23

First passageA

B Second passage

APP23 APP23

APP23

APP23

Aβ

(4G

8)A

β (4

G8)

Swedish AD

Swedish AD

Arctic AD

Arctic AD

Arctic AD

Arctic AD

Figure 3. Arctic and Swedish Alzheimer’s disease (AD) brain extracts induce distinct pathologies in APP23 mice.(A) Intracerebral inoculation of APP23 mice with brain extract from an AD patient with the Swedish APPmutation, which generates wild-type Ab, or brain extract from an AD patient with the Arctic APP mutation,which generates E22G-mutant Ab. At 11 mo postinoculation, induced Ab cerebral amyloid angiopathy ispresent in the thalamus (4G8 immunostaining). Whereas mice inoculated with Swedish AD extract exhibiteda thin layer of Ab deposition surrounding blood vessels (black arrows), many of the blood vessels in miceinoculated with Arctic AD extract were surrounded by thick, “furry” Ab deposits (red arrows). (B) Similarmorphological differences in Ab cerebral amyloid angiopathy were observed at 11 mo postinoculation of APP23mice with APP23-passaged Swedish and Arctic AD extract, indicating that Ab strain-specified properties areserially transmissible. Scale bars, 100 mm. (This figure has been adapted from Watts et al. 2014, with permissionfrom the National Academy of Sciences # 2014.)



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of distinct Ab strains among AD patients hasalso been demonstrated using brain extractsfrom two patients with early-onset familial ver-sions of the disease. Using a conformationalstability assay that measures the relative resis-tance of Ab aggregates to chemical denatura-tion, it was shown that the Ab aggregates froman AD patient with the Swedish mutation inAPP can be distinguished from those in an ADpatient with the Arctic mutation (E693G) (Nils-berth et al. 2001) in APP (Watts et al. 2014).When brain extracts from these two patientswere inoculated into APP23 mice, distinct vas-cular Abpathologies were observed (Fig. 3), andthese differences were maintained upon secondpassage in APP23 mice. These results reveal that,like PrP prions, strain-specific properties of Abprions are serially transmissible in mice.

CONCLUDING REMARKS

It is becoming increasingly clear that Ab prionsexhibit many similarities to prions composed ofPrP (Table 2), making it more difficult to refutethe notion that Ab can become a prion duringAD. However, there is currently minimal evi-

dence to suggest that Ab prions can be trans-mitted from human to human. Many individ-uals that received human cadaveric growthhormone injections ultimately died of CJD be-cause the pituitary extracts were contaminatedwith PrP prions (Brown et al. 2000). Althoughno increased incidence of AD has been observedin living individuals who received growth hor-mone injections (Irwin et al. 2013), it has re-cently been shown that the brains of growthhormone recipients who died of CJD containmuch higher levels of Ab deposition thanwould be expected (Jaunmuktane et al. 2015).One possible interpretation is that Ab prionswere present in the growth hormone extracts,which initiated cerebral Ab deposition follow-ing peripheral injection. Increased amounts ofAb deposition have also been observed in pa-tients that developed iatrogenic CJD followingdura mater grafts (Frontzek et al. 2016). Nota-bly, tau deposition was not observed in either ofthese instances, potentially indicating an earlystage of AD pathogenesis. Although iatrogenicAD transmission is only one potential explana-tion for these observations, sterilization meth-ods for surgical tools may need to be reconsid-

Table 2. Similarities and differences between PrP and Ab prions

Characteristic PrP prions Ab prions Reference(s) for Ab

Induction of protein aggregation in Tg miceexpressing mutant precursor protein

Yes Yes Kane et al. 2000; Meyer-Luehmann et al. 2006

Induction of protein aggregation in Tg miceexpressing wild-type precursor protein

Yes Yes Morales et al. 2012

Induction of protein aggregation in non-Tg mice Yes No Meyer-Luehmann et al. 2006Induction of protein aggregation in primates Yes Yes Ridley et al. 2006Induction of a lethal disease in mice Yes No Stohr et al. 2012Induction of neuronal loss in mice Yes No Ye et al. 2015bInduction of astrocytic gliosis in mice Yes Yes Watts et al. 2011Progressive spreading of protein aggregation Yes YesNeuroinvasion following peripheral inoculation Yes Yes Eisele et al. 2014Horizontal or iatrogenic transmission Yes Minimal

evidenceFrontzek et al. 2016

Zoonotic transmission Yes NoSerially transmissible Yes Yes Watts et al. 2014Existence of distinct strains Yes Yes Stohr et al. 2014Titratable levels of infectivity Yes Yes Morales et al. 2015Resistance to digestion with proteinase K Yes Yes Stohr et al. 2012Resistance to formaldehyde inactivation Yes Yes Fritschi et al. 2014aAdherence to stainless steel wires Yes Yes Eisele et al. 2009



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ered, especially because Ab prions remain activeonce bound to stainless steel (Eisele et al. 2009).

Although AD is unlikely to be transmissibleamong people under physiological circum-stances, the realization that Ab peptides can be-come prions during disease has many potentialimplications. First, the existence of self-propa-gating Ab prions may provide a molecular ex-planation for why AD is a progressive disorder.Spreading of Ab prions along neuroanatomicalpathways in conjunction with a potential stim-ulation of tau prion formation may cause a pro-gressive worsening of disease symptoms. More-over, like CJD, �90% of AD cases are sporadic,suggesting that the initiating event may be therare, age-related stochastic formation of a self-propagating Ab aggregate seed. In early-onsetfamilial AD, the necessity for Ab prion forma-tion may explain why disease most commonlymanifests in the fifth or sixth decade of life,despite the fact that elevated levels of pathogenicAb are produced from birth. Second, the for-mation of self-propagating Ab species may rep-resent an early event in disease progression thatcan be targeted pharmacologically. Third, theexistence of distinct strains of Ab prions posesa considerable challenge for the development ofAb-directed therapeutics for AD. Heterogeneityin the conformation of Ab aggregates may par-tially explain the disappointing results obtainedthus far in clinical trials of Ab monoclonal an-tibodies (Delrieu et al. 2012) because antibodyefficacy may be highly strain specific. Althoughstudies of the biology of Ab prions are still intheir infancy, they hold great promise for under-standing basic disease mechanisms and for thedevelopment of effective therapeutics for AD.

ACKNOWLEDGMENTS

The authors acknowledge support from the Ca-nadian Institutes of Health Research and theAlzheimer Society Canada (J.C.W.), as well asthe National Institutes of Health (AG002132and AG031220), Dana Foundation, GlennFoundation, Sherman Fairchild Foundation,and a gift from the Rainwater Charitable Foun-dation (S.B.P.).

REFERENCES

Baker HF, Ridley RM, Duchen LW, Crow TJ, Bruton CJ.1993. Evidence for the experimental transmission of ce-rebral b-amyloidosis to primates. Int J Exp Pathol 74:441–454.

Baker HF, Ridley RM, Duchen LW, Crow TJ, Bruton CJ.1994. Induction of b(A4)-amyloid in primates by injec-tion of Alzheimer’s disease brain homogenate. Mol Neu-robiol 8: 25–39.

Bard F, Cannon C, Barbour R, Burke RL, Games D, GrajedaH, Guido T, Hu K, Huang J, Johnson-Wood K, et al. 2000.Peripherally administered antibodies against amyloid b-peptide enter the central nervous system and reduce pa-thology in a mouse model of Alzheimer disease. Nat Med6: 916–919.

Benilova I, Karran E, De Strooper B. 2012. The toxic Aboligomer and Alzheimer’s disease: An emperor in needof clothes. Nat Neurosci 15: 349–357.

Bessen RA, Marsh RF. 1994. Distinct PrP properties suggestthe molecular basis of strain variation in transmissiblemink encephalopathy. J Virol 68: 7859–7868.

Brown P, Preece M, Brandel JP, Sato T, McShane L, Zerr I,Fletcher A, Will RG, Pocchiari M, Cashman NR, et al.2000. Iatrogenic Creutzfeldt–Jakob disease at the millen-nium. Neurology 55: 1075–1081.

Chartier-Harlin MC, Crawford F, Houlden H, Warren A,Hughes D, Fidani L, Goate A, Rossor M, Roques P, HardyJ, et al. 1991. Early-onset Alzheimer’s disease caused bymutations at codon 717 of the b-amyloid precursor pro-tein gene. Nature 353: 844–846.

Chishti MA, Yang DS, Janus C, Phinney AL, Horne P, Pear-son J, Strome R, Zuker N, Loukides J, French J, et al. 2001.Early-onset amyloid deposition and cognitive deficits intransgenic mice expressing a double mutant form of am-yloid precursor protein 695. J Biol Chem 276: 21562–21570.

Citron M, Oltersdorf T, Haass C, McConlogue L, Hung AY,Seubert P, Vigo-Pelfrey C, Lieberburg I, Selkoe DJ. 1992.Mutation of the b-amyloid precursor protein in familialAlzheimer’s disease increases b-protein production. Na-ture 360: 672–674.

Cohen RM, Rezai-Zadeh K, Weitz TM, Rentsendorj A, GateD, Spivak I, Bholat Y, Vasilevko V, Glabe CG, Breunig JJ, etal. 2013. A transgenic Alzheimer rat with plaques, taupathology, behavioral impairment, oligomeric Ab, andfrank neuronal loss. J Neurosci 33: 6245–6256.

Cohen ML, Kim C, Haldiman T, ElHag M, Mehndiratta P,Pichet T, Lissemore F, Shea M, Cohen Y, Chen W, et al.2015. Rapidly progressive Alzheimer’s disease featuresdistinct structures of amyloid-b. Brain 138: 1009–1022.

Colby DW, Prusiner SB. 2011. Prions. Cold Spring HarbPerspect Biol 3: a006833.

Collinge J, Clarke AR. 2007. A general model of prion strainsand their pathogenicity. Science 318: 930–936.

DeArmond SJ, Ironside JW, Bouzamondo-Bernstein E, Per-etz D, Fraser JR. 2004. Neuropathology of prion diseases.In Prion biology and diseases (ed. Prusiner SB), pp. 777–856. Cold Spring Harbor Laboratory Press, Cold SpringHarbor, NY.



ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



Delrieu J, Ousset PJ, Caillaud C, Vellas B. 2012. “Clinicaltrials in Alzheimer’s disease”: Immunotherapy approach-es. J Neurochem 120: 186–193.

De Strooper B, Iwatsubo T, Wolfe MS. 2012. Presenilins andg-secretase: Structure, function, and role in AlzheimerDisease. Cold Spring Harb Perspect Med 2: a006304.

Duran-Aniotz C, Morales R, Moreno-Gonzalez I, Hu PP,Soto C. 2013. Brains from non-Alzheimer’s individualscontaining amyloid deposits accelerate Ab deposition invivo. Acta Neuropathol Commun 1: 76.

Duran-Aniotz C, Morales R, Moreno-Gonzalez I, Hu PP,Fedynyshyn J, Soto C. 2014. Aggregate-depleted brainfails to induce Ab deposition in a mouse model of Alz-heimer’s disease. PLoS ONE 9: e89014.

Eisele YS, Bolmont T, Heikenwalder M, Langer F, JacobsonLH, Yan ZX, Roth K, Aguzzi A, Staufenbiel M, Walker LC,et al. 2009. Induction of cerebral b-amyloidosis: Intrace-rebral versus systemic Ab inoculation. Proc Natl Acad Sci106: 12926–12931.

Eisele YS, Obermuller U, Heilbronner G, Baumann F, KaeserSA, Wolburg H, Walker LC, Staufenbiel M, HeikenwalderM, Jucker M. 2010. Peripherally applied Ab-containinginoculates induce cerebral b-amyloidosis. Science 330:980–982.

Eisele YS, Fritschi SK, Hamaguchi T, Obermuller U, Fuger P,Skodras A, Schafer C, Odenthal J, Heikenwalder M, Stau-fenbiel M, et al. 2014. Multiple factors contribute to theperipheral induction of cerebral b-amyloidosis. J Neuro-sci 34: 10264–10273.

Fritschi SK, Cintron A, Ye L, Mahler J, Buhler A, Baumann F,Neumann M, Nilsson KP, Hammarstrom P, Walker LC, etal. 2014a. Ab seeds resist inactivation by formaldehyde.Acta Neuropathol 128: 477–484.

Fritschi SK, Langer F, Kaeser SA, Maia LF, Portelius E, Pi-notsi D, Kaminski CF, Winkler DT, Maetzler W, KeyvaniK, et al. 2014b. Highly potent soluble amyloid-b seeds inhuman Alzheimer brain but not cerebrospinal fluid.Brain 137: 2909–2915.

Frontzek K, Lutz MI, Aguzzi A, Kovacs GG, Budka H. 2016.Amyloid-b pathology and cerebral amyloid angiopathyare frequent in iatrogenic Creutzfeldt–Jakob disease afterdural grafting. Swiss Med Wkly 146: w14287.

Gajdusek DC, Gibbs CJ Jr, Alpers M. 1966. Experimentaltransmission of a kuru-like syndrome to chimpanzees.Nature 209: 794–796.

Gibbs CJ Jr, Gajdusek DC, Asher DM, Alpers MP, Beck E,Daniel PM, Matthews WB. 1968. Creutzfeldt–Jakob dis-ease (spongiform encephalopathy): Transmission to thechimpanzee. Science 161: 388–389.

Godec MS, Asher DM, Kozachuk WE, Masters CL, Rubi JU,Payne JA, Rubi-Villa DJ, Wagner EE, Rapoport SI, Scha-piro MB. 1994. Blood buffy coat from Alzheimer’s diseasepatients and their relatives does not transmit spongiformencephalopathy to hamsters. Neurology 44: 1111–1115.

Goudsmit J, Morrow CH, Asher DM, Yanagihara RT, Mas-ters CL, Gibbs CJ Jr, Gajdusek DC. 1980. Evidence forand against the transmissibility of Alzheimer’s disease.Neurology 30: 945–950.

Guardia-Laguarta C, Pera M, Clarimon J, Molinuevo JL,Sanchez-Valle R, Llado A, Coma M, Gomez-Isla T, BlesaR, Ferrer I, et al. 2010. Clinical, neuropathologic, and

biochemical profile of the amyloid precursor proteinI716F mutation. J Neuropathol Exp Neurol 69: 53–59.

Haass C, Lemere CA, Capell A, Citron M, Seubert P, SchenkD, Lannfelt L, Selkoe DJ. 1995. The Swedish mutationcauses early-onset Alzheimer’s disease by b-secretasecleavage within the secretory pathway. Nat Med 1:1291–1296.

Hamaguchi T, Eisele YS, Varvel NH, Lamb BT, Walker LC,Jucker M. 2012. The presence of Ab seeds, and not age perse, is critical to the initiation of Ab deposition in thebrain. Acta Neuropathol 123: 31–37.

Hardy J, Selkoe DJ. 2002. The amyloid hypothesis of Alz-heimer’s disease: Progress and problems on the road totherapeutics. Science 297: 353–356.

Hebert LE, Weuve J, Scherr PA, Evans DA. 2013. Alzheimerdisease in the United States (2010–2050) estimated usingthe 2010 census. Neurology 80: 1778–1783.

Heilbronner G, Eisele YS, Langer F, Kaeser SA, Novotny R,Nagarathinam A, Aslund A, Hammarstrom P, Nilsson KP,Jucker M. 2013. Seeded strain-like transmission of b-am-yloid morphotypes in APP transgenic mice. EMBO Rep14: 1017–1022.

Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Youn-kin S, Yang F, Cole GJ. 1996. Correlative memory deficits,Ab elevation, and amyloid plaques in transgenic mice.Science 274: 99–102.

Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houl-den H, Pickering-Brown S, Chakraverty S, Isaacs A,Grover A, et al. 1998. Association of missense and 50-splice-site mutations in tau with the inherited dementiaFTDP-17. Nature 393: 702–705.

Irwin DJ, Abrams JY, Schonberger LB, Leschek EW, Mills JL,Lee VM, Trojanowski JQ. 2013. Evaluation of potentialinfectivity of Alzheimer and Parkinson disease proteinsin recipients of cadaver-derived human growth hormone.JAMA Neurol 70: 462–468.

Janus C, Pearson J, McLaurin J, Mathews PM, Jiang Y,Schmidt SD, Chishti MA, Horne P, Heslin D, French J,et al. 2000. Ab peptide immunization reduces behav-ioural impairment and plaques in a model of Alzheimer’sdisease. Nature 408: 979–982.

Jaunmuktane Z, Mead S, Ellis M, Wadsworth JDF, Nicoll AJ,Kenny J, Launchbury F, Linehan J, Richard-Loendt A,Walker AS, et al. 2015. Evidence for human transmissionof amyloid-b pathology and cerebral amyloid angiop-athy. Nature 525: 247–250.

Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV,Bjornsson S, Stefansson H, Sulem P, Gudbjartsson D,Maloney J, et al. 2012. A mutation in APP protects againstAlzheimer’s disease and age-related cognitive decline.Nature 488: 96–99.

Jucker M. 2010. The benefits and limitations of animal mod-els for translational research in neurodegenerative dis-eases. Nat Med 16: 1210–1214.

Kane MD, Lipinski WJ, Callahan MJ, Bian F, Durham RA,Schwarz RD, Roher AE, Walker LC. 2000. Evidence forseeding of b-amyloid by intracerebral infusion of Alz-heimer brain extracts in b-amyloid precursor protein-transgenic mice. J Neurosci 20: 3606–3611.

Kodali R, Williams AD, Chemuru S, Wetzel R. 2010. Ab(1–40) forms five distinct amyloid structures whose b-sheet



ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



contents and fibril stabilities are correlated. J Mol Biol401: 503–517.

Langer F, Eisele YS, Fritschi SK, Staufenbiel M, Walker LC,Jucker M. 2011. Soluble Ab seeds are potent inducers ofcerebral b-amyloid deposition. J Neurosci 31: 14488–14495.

Lu JX, Qiang W, Yau WM, Schwieters CD, Meredith SC,Tycko R. 2013. Molecular structure of b-amyloid fibrilsin Alzheimer’s disease brain tissue. Cell 154: 1257–1268.

Maia LF, Kaeser SA, Reichwald J, Hruscha M, Martus P,Staufenbiel M, Jucker M. 2013. Changes in amyloid-band tau in the cerebrospinal fluid of transgenic mice over-expressing amyloid precursor protein. Sci Transl Med 5:194re2.

Manuelidis EE, de Figueiredo JM, Kim JH, Fritch WW,Manuelidis L. 1988. Transmission studies from blood ofAlzheimer disease patients and healthy relatives. ProcNatl Acad Sci 85: 4898–4901.

Meinhardt J, Sachse C, Hortschansky P, Grigorieff N, Fan-drich M. 2009. Ab(1–40) fibril polymorphism impliesdiverse interaction patterns in amyloid fibrils. J Mol Biol386: 869–877.

Meyer-Luehmann M, Coomaraswamy J, Bolmont T, KaeserS, Schaefer C, Kilger E, Neuenschwander A, AbramowskiD, Frey P, Jaton AL, et al. 2006. Exogenous induction ofcerebral b-amyloidogenesis is governed by agent andhost. Science 313: 1781–1784.

Morales R, Duran-Aniotz C, Castilla J, Estrada LD, Soto C.2012. De novo induction of amyloid-b deposition invivo. Mol Psychiatry 17: 1347–1353.

Morales R, Bravo-Alegria J, Duran-Aniotz C, Soto C. 2015.Titration of biologically active amyloid-b seeds in a trans-genic mouse model of Alzheimer’s disease. Sci Rep 5:9349.

Morrissette DA, Parachikova A, Green KN, LaFerla FM.2009. Relevance of transgenic mouse models to humanAlzheimer disease. J Biol Chem 284: 6033–6037.

Mullan M, Crawford F, Axelman K, Houlden H, Lilius L,Winblad B, Lannfelt L. 1992. A pathogenic mutation forprobable Alzheimer’s disease in APP gene at the N-ter-minus of b-amyloid. Nat Genet 1: 345–347.

Murrell J, Farlow M, Ghetti B, Benson MD. 1991. A muta-tion in the amyloid precursor protein associated withhereditary Alzheimer’s disease. Science 254: 97–99.

Nilsberth C, Westlind-Danielsson A, Eckman CB, CondronMM, Axelman K, Forsell C, Stenh C, Luthman J, TeplowDB, Younkin SG, et al. 2001. The ‘Arctic’ APP mutation(E693G) causes Alzheimer’s disease by enhanced Ab pro-tofibril formation. Nat Neurosci 4: 887–893.

Paravastu AK, Leapman RD, Yau WM, Tycko R. 2008. Mo-lecular structural basis for polymorphism in Alzheimer’sb-amyloid fibrils. Proc Natl Acad Sci 105: 18349–18354.

Paravastu AK, Qahwash I, Leapman RD, Meredith SC, TyckoR. 2009. Seeded growth of b-amyloid fibrils from Alz-heimer’s brain-derived fibrils produces a distinct fibrilstructure. Proc Natl Acad Sci 106: 7443–7448.

Petkova AT, Leapman RD, Guo Z, Yau WM, Mattson MP,Tycko R. 2005. Self-propagating, molecular-level poly-morphism in Alzheimer’s b-amyloid fibrils. Science307: 262–265.

Prusiner SB. 1982. Novel proteinaceous infectious particlescause scrapie. Science 216: 136–144.

Prusiner SB. 1984. Some speculations about prions, amy-loid, and Alzheimer’s disease. N Engl J Med 310: 661–663.

Prusiner SB. 2012. A unifying role for prions in neurode-generative diseases. Science 336: 1511–1513.

Prusiner SB, McKinley MP, Bowman KA, Bolton DC, Bend-heim PE, Groth DF, Glenner GG. 1983. Scrapie prionsaggregate to form amyloid-like birefringent rods. Cell 35:349–358.

Radde R, Bolmont T, Kaeser SA, Coomaraswamy J, LindauD, Stoltze L, Calhoun ME, Jaggi F, Wolburg H, Gengler S,et al. 2006. Ab42-driven cerebral amyloidosis in trans-genic mice reveals early and robust pathology. EMBO Rep7: 940–946.

Ridley RM, Baker HF, Windle CP, Cummings RM. 2006.Very long term studies of the seeding of b-amyloidosisin primates. J Neural Transm 113: 1243–1251.

Rosen RF, Fritz JJ, Dooyema J, Cintron AF, Hamaguchi T,Lah JJ, Levine H 3rd, Jucker M, Walker LC. 2012. Exog-enous seeding of cerebral b-amyloid deposition inbAPP-transgenic rats. J Neurochem 120: 660–666.

Rovelet-Lecrux A, Hannequin D, Raux G, Le Meur N, La-querriere A, Vital A, Dumanchin C, Feuillette S, Brice A,Vercelletto M, et al. 2006. APP locus duplication causesautosomal dominant early-onset Alzheimer disease withcerebral amyloid angiopathy. Nat Genet 38: 24–26.

Saito T, Matsuba Y, Mihira N, Takano J, Nilsson P, Itohara S,Iwata N, Saido TC. 2014. Single App knock-in mousemodels of Alzheimer’s disease. Nat Neurosci 17: 661–663.

Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H,Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, etal. 1999. Immunization with amyloid-b attenuates Alz-heimer-disease-like pathology in the PDAPP mouse. Na-ture 400: 173–177.

Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G,Ikeda M, Chi H, Lin C, Li G, Holman K, et al. 1995.Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 375: 754–760.

Sigurdson CJ, Nilsson KP, Hornemann S, Manco G, Poly-menidou M, Schwarz P, Leclerc M, Hammarstrom P,Wuthrich K, Aguzzi A. 2007. Prion strain discriminationusing luminescent conjugated polymers. Nat Methods 4:1023–1030.

Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug A,Ghetti B. 1998. Mutation in the tau gene in familial mul-tiple system tauopathy with presenile dementia. Proc NatlAcad Sci 95: 7737–7741.

Stohr J, Watts JC, Mensinger ZL, Oehler A, Grillo SK, DeAr-mond SJ, Prusiner SB, Giles K. 2012. Purified and syn-thetic Alzheimer’s amyloidb (Ab) prions. Proc Natl AcadSci 109: 11025–11030.

Stohr J, Condello C, Watts JC, Bloch L, Oehler A, Nick M,DeArmond SJ, Giles K, DeGrado WF, Prusiner SB. 2014.Distinct synthetic Ab prion strains producing differentamyloid deposits in bigenic mice. Proc Natl Acad Sci 111:10329–10334.

Sturchler-Pierrat C, Abramowski D, Duke M, WiederholdKH, Mistl C, Rothacher S, Ledermann B, Burki K, Frey P,Paganetti PA, et al. 1997. Two amyloid precursor protein



ww

w.p

ersp

ecti

vesi

nm

edic

ine.

org



transgenic mouse models with Alzheimer disease-likepathology. Proc Natl Acad Sci 94: 13287–13292.

Suzuki N, Cheung TT, Cai XD, Odaka A, Otvos L Jr, EckmanC, Golde TE, Younkin SG. 1994. An increased percentageof long amyloid b protein secreted by familial amyloidb protein precursor (b APP717) mutants. Science 264:1336–1340.

Telling GC, Parchi P, DeArmond SJ, Cortelli P, Montagna P,Gabizon R, Mastrianni J, Lugaresi E, Gambetti P, PrusinerSB. 1996. Evidence for the conformation of the patho-logic isoform of the prion protein enciphering and prop-agating prion diversity. Science 274: 2079–2082.

Thal DR, Rub U, Orantes M, Braak H. 2002. Phases of Ab-deposition in the human brain and its relevance for thedevelopment of AD. Neurology 58: 1791–1800.

Watts JC, Giles K, Grillo SK, Lemus A, DeArmond SJ, Pru-siner SB. 2011. Bioluminescence imaging of Ab deposi-tion in bigenic mouse models of Alzheimer’s disease. ProcNatl Acad Sci 108: 2528–2533.

Watts JC, Condello C, Stohr J, Oehler A, Lee J, DeArmondSJ, Lannfelt L, Ingelsson M, Giles K, Prusiner SB. 2014.Serial propagation of distinct strains of Ab prions fromAlzheimer’s disease patients. Proc Natl Acad Sci 111:10323–10328.

Wisniewski KE, Wisniewski HM, Wen GY. 1985. Occur-rence of neuropathological changes and dementia of Alz-heimer’s disease in Down’s syndrome. Ann Neurol 17:278–282.

Ye L, Hamaguchi T, Fritschi SK, Eisele YS, Obermuller U,Jucker M, Walker LC. 2015a. Progression of seed-inducedAb deposition within the limbic connectome. BrainPathol 25: 743–752.

Ye L, Fritschi SK, Schelle J, Obermuller U, Degenhardt K,Kaeser SA, Eisele YS, Walker LC, Baumann F, StaufenbielM, et al. 2015b. Persistence of Ab seeds in APP nullmouse brain. Nat Neurosci 18: 1559–1561.

Zhu L, Ramboz S, Hewitt D, Boring L, Grass DS, Purchio AF.2004. Non-invasive imaging of GFAP expression afterneuronal damage in mice. Neurosci Lett 367: 210–212.



ww

w.p

ersp

ecti

vesi

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published online February 13, 2017Cold Spring Harb Perspect Med Joel C. Watts and Stanley B. Prusiner -Amyloid Prions and the Pathobiology of Alzheimer's Diseaseβ

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