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The -Like Properties of -b Assemblies: Implications for Alzheimer’s

Lary C. Walker,1 Juliane Schelle,2,3 and Mathias Jucker2,3

1Yerkes National Primate Research Center and Department of , Emory University, Atlanta, Georgia 30322 2Department of Cellular Neurology, Hertie Institute for Clinical Research, University of Tu¨bingen, D-72076 Tu¨bingen, Germany 3German Center for Neurodegenerative (DZNE), D-72076 Tu¨bingen, Germany Correspondence: [email protected]; [email protected]

Since the discovery that prion diseases can be transmitted to experimental animals by inoc- ulation with afflicted brain matter, researchers have speculated that the of patients suffering from other neurodegenerative diseases might also harbor causative agents with transmissible properties. Foremost among these disorders is Alzheimer’s disease (AD), the most common cause of in the elderly. A growing body of research supports the concept that the pathogenesis of AD is initiated and sustained by the endogenous, seeded misfolding and aggregation of the fragment amyloid-b (Ab). At the molecular level, this mechanism of nucleated protein self-assembly is virtually identical to that of consisting of the prion protein (PrP). The formation, propagation, and spread of Ab seeds within the brain can thus be considered a fundamental feature of AD pathogenesis.

lzheimer’s disease (AD) is the most frequent fining components of plaques are extracellular Acause of dementia and a growing social, collections of aggregated Ab protein, whereas medical, and economic challenge to societies NFTs consist of intracellular bundles of hyper- in which the elderly population is rapidly grow- phosphorylated (Duyckaerts et al. ing (Dartigues 2009; Holtzman et al. 2011; Reitz 2009; Holtzman et al. 2011). In both cases, the www.perspectivesinmedicine.org et al. 2011). The involvement of abnormal pro- that accumulate assume a tertiary teins in AD has been evident since Alois Alz- structure (or fold) that is unusually rich in b- heimer’s original histopathological descriptions sheet, which in turn promotes the structural of the disease in the early 20th century (Alz- corruption and self-assembly of like molecules heimer 1906). Even today, a conclusive diagno- into small oligomeric and larger fibrillar assem- sis of AD in a patient with dementia requires the blies with neurotoxic properties (Haass and Sel- significant presence of two cardinal brain le- koe 2007; Klein 2013). The resulting aggregates sions at autopsy: amyloid-b (Ab) plaques and have features that are often characteristic of am- neurofibrillary tangles (NFTs) (Fig. 1). The de- yloid (Eisenberg and Jucker 2012). Although

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Figure 1. The canonical of Alzheimer’s disease (AD). Amyloid-b (Ab) plaques consist of extracellular deposits of Ab (brown; detected by with a polyclonal antibody to Ab), and neurofibrillary tangles (NFTs) consist of intracellular masses of ectopic tau protein (purple; detected by im- munostaining with a monoclonal antibody to tau). Scale bar, 100 mm.

the presence of amyloid signifies a proteopathic specific manner (Braak and Braak 1991; Thal process, amyloid per se is not always required et al. 2002; Jucker and Walker 2013). In addition for the complete manifestation of disease. Both to these pathological hallmarks and diagnostic Ab plaques (Fig. 2) and tau lesions can be mod- lesions, the AD brain is typified by impaired eled in transgenic mice (Jucker 2010). With the synaptic function, neuroinflammation, and progression of AD, Ab deposition and NFTs neuronal loss, which ultimately contribute to increase in number and affect large areas of the full expression of dementia (Holtzman the brain in a characteristic and brain region– et al. 2011; Nelson et al. 2012).

AB www.perspectivesinmedicine.org

Figure 2. Similar appearance of amyloid-b (Ab) deposits in the brain of an Alzheimer’s disease (AD) patient and an Ab-precursor protein (APP)-transgenic mouse model. (A)Ab deposits in the of an AD patient. (B)Ab deposits in the neocortex of an APP23 transgenic mouse. An anti-Ab specific polyclonal antibody (black) was used for immunostaining. Sections were counterstained with , a generic stain for amyloid. Scale bar, 200 mm.

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Prion-Like Properties of Aggregated Ab

In addition to plaques, Ab accumulates to a autosomal dominant causative mutations and variable extent in the walls of cerebral blood ves- in subjects with idiopathic AD before the likely sels in AD patients; this cerebral amyloid angi- age of dementia onset shows that Ab changes in opathy (CAA) of the Ab-type, although not the brain are the first harbinger of impending pathognomonic for AD, is a risk factor for hem- disease, and that this can occur decades before orrhagic stroke (Yamada 2013) and can inde- clinical dementia sets in (Jack et al. 2010; Holtz- pendently contribute to cognitive decline (Biffi man et al. 2011; Selkoe 2011; Bateman et al. and Greenberg 2011; Reijmer et al. 2015). More- 2012). These findingstogether highlight the piv- over, in most cases of AD (particularly in older otal role of Ab in the pathogenesis of AD. patients), typical pathological features are ac- companied by variable amounts of comorbid EXPERIMENTAL EVIDENCE FOR THE PRION- lesions, such as vascular abnormalities and/or LIKE SEEDING OF Ab AGGREGATION aggregates of other, non-AD-specific patho- genic proteins such as a-synuclein, TDP-43, Since the discovery that prion diseases can be and others (Neuropathology Group, Medical transmitted to experimental animals by inocu- Research Council Cognitive Function and Aging lation with afflicted brain fractions, researchers Study 2001; Knopman et al. 2003; Schneider have speculated that the brains of patients suf- et al. 2007; Nelson et al. 2012). fering from other neurodegenerative diseases might also harbor causative agents with trans- missible properties (Prusiner 1984; Gajdusek THE PRIMACY OF Ab IN THE AD 1994). A team in Great Britain reported that PATHOGENIC CASCADE Ab load is increased in the brains of nonhuman Although the degree of correlates primates by the intracerebral injection of AD more strongly with cognitive decline than does brain homogenates (Baker et al. 1993). Howev- the buildup of Ab (Giannakopoulos et al. 2003), er, the experiments required an incubation pe- extant evidence indicates that in AD (Hardy and riod of .5 yr, and the causative agent and Selkoe 2002; Holtzman et al. 2011; Nelson et al. mechanism of action remained uncertain. In 2012) and in genetically modified mice (Go¨tz the late 1990s, as the first transgenic mouse et al. 2001; Lewis et al. 2001; Bolmont et al. models of cerebral b- became avail- 2007; He´raud et al. 2014; Stancu et al. 2014; Vas- able (Games et al. 1995; Hsiao et al. 1996; concelos et al. 2016), tauopathy is downstream Sturchler-Pierrat et al. 1997), we set out to de- from Ab . Moreover, the genetic finitively test the hypothesis that the prion par- causes of autosomal dominant AD identified adigm of nucleated protein self-assembly also www.perspectivesinmedicine.org so far all affect Ab by enhancing its release applies to Ab. This series of studies, in conjunc- from the Ab-precursor protein (APP) or its ten- tion with investigations in other laboratories, dency toself-aggregate(HardyandSelkoe2002). now provides support for the concept that the In contrast, a rare mutation in the APP gene that molecular properties of pathogenic Ab assem- causes an substitution at position 2 blies are virtually identical to those of prion of Ab (A673Taccording to APP770 numbering) protein (PrP) prions (Walker and Jucker 2015). reduces the production of Ab following b- In our first experiments, extracts of autopsy- secretase cleavage (Jonsson et al. 2012) and also derived brain samples from AD patients and lowers the propensity of Ab to aggregate (Beni- controls were injected stereotaxically into the lova et al. 2014); the A673T mutation thereby hippocampal formation and/or neocortex of also lessens the risk of developing AD (Jonsson young, predepositing APP-transgenic mice et al. 2012). Substitution of valine for alanine at (Kane et al. 2000; Walker et al. 2002; Meyer- this site (A673V) enhances the production and Luehmann et al. 2006). After incubation periods aggregation of Ab and causes an autosomal re- ranging from a few hours to 12 mo, the brains cessive form of AD (Di Fede et al. 2009). Further- were analyzed immunohistochemically. Because more, assessment of biomarkers in subjects with only small amounts of extract were injected

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(typically1–2.5 mL, containing 10 ng Ab/mL), extract (Meyer-Luehmann et al. 2006; Fritschi little or no immunohistochemically detectable etal.2014b).SeededAbdepositsarebothdiffuse Ab remained after a few days or more of incu- and congophilic, and dense-core (congophilic) bation. However, by 3 to 5 mo postsurgery, at a plaques are associated with cellular reactivity point when the transgenic mice had not yet be- that includes microgliosis, astrocytosis, and ab- gun to form endogenous Ab plaques and CAA, normal containing increased APP and Ab deposits emerged and increased dramati- hyperphosphorylated tau. Importantly, no Ab cally with longer incubation intervals (Fig. 3). deposits emerged in nontransgenic host mice, The degree of Ab-seeding in mice is directly and brain extracts from non-AD control donors proportional to the concentration of the brain that lacked Ab deposition did not induce signif-

A B

Incubation Inoculation with 6 mo 12 mo brain extract containing aggregated Aβ

AP +2.2 mm

AP +0.1 mm www.perspectivesinmedicine.org

AP –1.8 mm

AP –3.3 mm

Figure 3. Induction and spread of amyloid-b (Ab) lesions in an Ab-precursor protein (APP)-transgenic mouse model. Ab seed-laden brain extract was bilaterally injected into the and overlying neocortex of R1.40 APP-transgenic mice. The injection site is marked in purple. (A) After a 6-mo incubation period, Ab deposition appeared mainly in the hippocampus. (B) After a 12-mo incubation period, spreading of Ab deposition to neighboring brain regions and throughout much of the forebrain was observed. (From Fritschi et al. 2013; modified with the authors’ permission.)

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Prion-Like Properties of Aggregated Ab

icant Ab lesions (Kane et al. 2000; Meyer-Lueh- Ab seeds, then, like PrP prions, gain consider- mann et al. 2006). NFTs per se have not been able potency when formed within the brain. The detected in seeded APP-transgenic mouse mod- seeded conversion of synthetic Ab into potent, els and would likely require the expression of in vivo–active Ab seeds has recently been -sequence tau in host mice (Bolmont achieved in a hippocampal slice culture model et al. 2007). (Novotny et al. 2016). Further deciphering of These findings indicate that Ab seeding re- the factors responsible for the conversion will quires both a donor brain extract that contains be important to understanding the pathogenic- Ab seeds and a host that is capable of generating ity of multimeric Ab in AD. For instance, the Ab plaques and/or CAA of the Ab type. addition of certain cofactors to the medium in Because injections of control brain extracts which synthetic PrP is aggregated augments the failed to seed plaque formation, these findings seeding potential of synthetic PrP prions (Wang also mitigate against the possibility that the in- et al. 2010; Deleault et al. 2012; Zhang et al. duction of Ab deposition is simply caused by 2014). It will be informative to determine brain injury. The concern that the seeding effect whethercofactors might also increase the poten- might result from factors in the cy of synthetic Ab seeds. that indirectly stimulate Ab aggregation, such as a human-specific virus or an immune response THE INTERACTION OF Ab STRAINS to the foreign brain fractions, was ruled out by a AND HOST FACTORS robust seeding response to Ab-rich brain ex- tracts from aged APP transgenic donor mice To induce Ab deposition in the in vivo seeding of the same strain as the host mice (Meyer- model, it is necessary for the host animal to Luehmann et al. 2006; Watts et al. 2011). express seeding-capable Ab (Kane et al. 2000; The next step was to define the nature of the Meyer-Luehmann et al. 2006; Morales et al. Ab seeds. Denaturation of brain extracts with 2012; Rosen et al. 2012). In earlier studies, trans- formic acid (Meyer-Luehmann et al. 2006), or genic mouse models that eventually develop the specific depletion of Ab by antibodies or endogenous Ab lesions as they age were used. reagents that bind and remove amyloid proteins Prion disease, however, is induced de novo by from the extract, abrogated the seeding effect with PrP prions in animals that oth- (Meyer-Luehmann et al. 2006; Duran-Aniotz erwise would never have manifested the disease. et al. 2014). Seeding was also blocked when the To determine whether Ab deposits can also be extract was mixed with an Ab antibody and then generated de novo in relatively resistant animals, injected into the brain (Meyer-Luehmann et al. Ab-seeding experiments were undertaken in www.perspectivesinmedicine.org 2006). APP-transgenic mice (Morales et al. 2012) and These results confirmed that Ab is essential rats (Rosen et al. 2012) that do not generate to the seeding capacityof brain extracts, but they plaques or CAA within their normal life spans. left open the question of whether pure, aggre- In both instances, Ab deposition was induced gated, synthetic Ab is able to induce deposition in the brain after a suitable incubation period. in mice. In early experiments, the injection of The existence of variant structural strains of various amounts of synthetic Ab fibrils did not Ab is increasingly well established (Eisenberg cause obvious induction of new plaques up to and Jucker 2012; Lu et al. 2013; Hatami et al. 5 mo postinjection (Meyer-Luehmann et al. 2014;Spirigetal.2014;Cohenetal.2015).Grow- 2006). This finding was not entirely unexpected, ing evidence supports the hypothesis that Ab given the poor potency of recombinant PrP in seeds, like PrP prions (Aguzzi et al. 2007; Col- inducing brain disease (Legname et al. 2004). linge and Clarke 2007; Prusiner 2013), can also More recently, however, it was shown that with adopt different molecular conformations that a larger dose of aggregated Ab and a longer in- are linked to their functionality in vivo (Meyer- cubation time, Ab deposition can be instigated Luehmann et al. 2006; Eisenberg and Jucker by multimeric, synthetic Ab (Sto¨hr et al. 2012). 2012; Sto¨hr et al. 2014; Watts et al. 2014).

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APP-transgenic mice (APP23 mice) and trans- Ab was in the soluble fraction. Therefore, small, genicmice expressinghumanAPPalongwith hu- soluble Ab assemblies, like small PrP prions, are man presenilin-1 (APPPS1 mice) develop paren- highly effective seeds. Given their limited di- chymal Ab deposits that differ morphologically mensions, it is conceivable that soluble Ab seeds at the light-microscopic level (Heilbronner et al. traffic through the brain more readily than do 2013). When Ab-laden brain extract from one larger fibrils. Interestingly, these soluble seeds, model was injected intracerebrally into the other unlike insoluble multimers, are quite sensitive model, the lesion morphologies, as revealed by to destruction by proteinase K (PK), suggesting , and the molecular that they may be particularly susceptible to ther- architecture of the deposited Ab, as assessed apeutic intervention (Langer et al. 2011). by amyloid conformation-sensitive oligothio- To assess the potency of Ab seeds in stimu- phene dyes, showed characteristics of both the lating cerebral Ab-deposition, serially diluted host and seeding extract (Heilbronner et al. brain extracts from autopsied AD patients 2013). Interestingly, the ratio of Ab40 to Ab42 were injected into the hippocampus of young, in the induced Ab deposits in host mice also was APP-transgenic host mice. The degree of induc- influenced by exogenous seeds, suggesting that tion diminished with increasing dilution, but this ratio may contribute to the strain-like prop- even subattomolar levels of brain-derived Ab erties of Abassemblies (Heilbronneret al. 2013). were found to stimulate Ab-proteopathy in Transmission studies have found that brain ex- the hosts (Fritschi et al. 2014b). In a recent ex- tractsfromADpatientscarryingeithertheSwed- periment, Ab seed–rich brain extracts were in- ish or Arctic mutation injected into the brains of jected into APP-null host mice that, because of susceptible mice induced distinct Ab patholo- the absence of Ab, are incapable of replicating gies that could be serially propagated and main- Ab seeds; 6 mo later, brain extracts from these tained after multiple passages (Watts et al. 2014). APP-null mice were still able to seed Ab depo- Finally, in a given host model, if seeds are infused sition in APP-transgenic hosts, indicative of ex- into brain regions other than the hippocampus, traordinary potency and of Ab seeds the deposits that emerge are often typical of (Ye et al. 2015a). Surprisingly, Ab in the cere- the morphotypes displayed by the endogenous brospinal fluid (CSF) of AD patients and aged (unseeded) lesions that form in the respective APP-transgenic donor mice was devoid of sig- structures as the mice age (Eisele et al. 2009). nificant in vivo seeding activity, even at levels of Hence,not only the host mouse but also the local Ab exceeding those in the most concentrated brain conditions influence the types of lesions brain extracts (Fritschi et al. 2014b). The rea- that are induced by exogenous Ab seeds. sons for the inability of Ab in the CSF to seed in www.perspectivesinmedicine.org vivo remain uncertain, but the mechanism could reveal a novel means of impeding the THE SIZE AND POTENCY OF Ab SEEDS seeding cascade in the brain. Prions exist in a range of sizes, and the most potent PrP prions appear to be small, soluble THE ROBUSTNESS OF Ab SEEDS species (Silveira et al. 2005). To assess the size range of Ab seeds, brain extracts were subjected Although PrP prions vary in their stability to ultracentrifugation (100,000Âg for 1 h). (Tzaban et al. 2002; Choi et al. 2010; Zou et al. Most (.99%) of the Ab from the extract sed- 2010; Gambetti et al. 2011), a notable charac- iments in the pellet, which, when injected intra- teristic of infectious prions is that some of them cerebrally into mice, seeds Ab aggregation al- are quite durable, even under harsh environ- most as effectively as does the original brain mental conditions (Appel et al. 2001; Wiggins extract. Surprisingly, however, soluble Ab in 2009). The ability of these prions to retain their the high-speed supernatant seeded 30% as pathogenic properties contributes to their in- much histochemically detectable Ab deposition fectivity, including rare instances of infection as did the insoluble pellet, although ,1% of the in neurosurgical patients exposed to PrP

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Prion-Like Properties of Aggregated Ab

prion–contaminated surgical instruments that APP-transgenic hosts. The fixed brain samples had been sterilized via conventional methods retained their seeding potential, even after as (Brown et al. 2012; Thomas et al. 2013). Studies long as 2 yr in formaldehyde (Fritschi et al. in experimental animals confirm the persistent 2014a). Additionally, the spectral patterns of lu- infectivity of PrP prions bound to stainless-steel minescent conjugated oligothiophenes bound wire (Flechsig et al. 2001), even after the wire to Ab indicated that the molecular architecture has been exposed to formaldehyde (Zobeley of the Ab seeds was maintained in fixed tissue et al. 1999). and could be faithfully transmitted to the host A first hint that Ab seeds are also durable mice (Fritschi et al. 2014a). agents came from studies in which Ab-rich brain extract was boiled for 5 min and still re- tained its seeding capacity (Meyer-Luehmann et TRAFFICKING OF Ab SEEDS al. 2006). In later studies drawing from work in Trafficking within the Brain the PrP prion field, a minute quantity of Ab- rich brain extract was dried onto stainless-steel PrP prion–laden extracts injected into the wires, and the wires were implanted in the brains of transgenic mice yield that brains of APP-transgenic host mice (Eisele et is not restricted to the injection site; rather, the al. 2009). After an incubation period of 4 mo, PrP prions propagate and spread throughout Ab lesions were induced in the region immedi- most of the brain (Fraser 1982; Buyukmihci ately surrounding the wire and, to a lesser ex- et al. 1983; Kimberlin and Walker 1986; Liberski tent, in more distant areas. Plasma sterilization et al. 2012; Rangel et al. 2014). In the case of AD, of the contaminated wires before implantation the neuroanatomical distribution of plaques prevented plaque induction, but heating them and tangles at different disease stages suggests for 10 min at 95˚C did not (Eisele et al. 2009). that the lesions propagate among axonally con- Although this study suggests that Ab seeds on nected brain areas (Saper et al. 1987; Arnold insufficiently sterilized surgical instruments et al. 1991; Braak and Braak 1995), a possibility might increase the risk of AD, presently this is that is garnering support from contemporary only a theoretical possibility. imaging modalities (Bero et al. 2011; Zhou One of the first clues that the agent that et al. 2012; Iturria-Medina et al. 2014; Raj et al. transmits PrP prion disease is highly unortho- 2015). Experimentally, within 24 h of injecting dox surfaced unexpectedly in the 1930s when Ab-rich brain extract into the hippocampus, William Gordon immunized sheep against a vi- immunohistochemical examination shows that ral illness called louping-ill (Gordon 1946). The the extract diffuses away from the injection site www.perspectivesinmedicine.org vaccine was prepared from formaldehyde-fixed and tends to concentrate along the hippocampal nervous tissue derived from sheep that had been fissure, around blood vessels, and in the subpial sick with louping-ill. Although the vaccine zone, regions that exhibit a strong seeding re- worked well to reduce the incidence of loup- sponse following a much longer incubation pe- ing-ill, after several years the vaccinated sheep riod (Walker et al. 2002; Ye et al. 2015b). The began to develop scrapie. Gordon surmised that injected Ab rapidly becomes undetectable his- some of the sheep used to prepare the vaccine tochemically, and a lag period ensues before the were also incubating the scrapie agent and that focal emergence of induced deposits in the in- the agent is resistant to inactivation by formal- jected hippocampus, usually after a month or dehyde (Gordon 1946). This conclusion has more depending on the mouse model (Kane been supported by subsequent research (Patti- et al. 2000; Meyer-Luehmann et al. 2006; Eisele son 1965; Brown et al. 1990). et al. 2014). Over time, Ab depositsthen begin to Todetermine whether Ab seeds are similarly appear in other brain regions, most notably in resistant to formaldehyde inactivation, formal- the entorhinal cortex ventrolateral to the dorsal dehyde-fixed brain samples from AD patients hippocampal injection site (Walker et al. 2002; and APP-transgenic mice were injected into Meyer-Luehmann et al. 2006; Eisele et al. 2009).

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When the seeds are placed in the entorhinal that exogenous Ab seeds (and their endogenous cortex, the earliest secondary deposits emerge descendants) can translocate by other means. In selectively in the hippocampal formation (Eisele mice seeded intrahippocampally with Ab-rich et al. 2009). Because the entorhinal cortex is a brain extracts, we have noted the premature ap- major source of neocortical communication pearance of CAA in the thalamus (Meyer-Lueh- with the hippocampal formation (Suh et al. mann et al. 2006). How thalamic CAA is stimu- 2011; Arszovszki et al. 2014), these studies pro- lated in hippocampally seeded mice remains vided the first clues that neuronal pathways unknown. In this light, alternative modes of might define the spread of Ab pathology seed trafficking, beyond passive diffusion and through the brain. neuronal transport, should be considered. These To further test the hypothesis that Ab seeds include perivascular and paravascular flow propagate by sequential seeding requires ex- (Weller et al. 1998; Thal et al. 2007; Iliff et al. tending the incubation period into the age 2012) or uptake and transport by nonneuronal when most transgenic mouse models begin to cells such as macrophages (Eisele et al. 2009) (see generate deposits on their own. For this pur- below). pose, the R1.40 APP-transgenic mouse model (Lamb et al. 1997) was used. These mice do not Trafficking from the Periphery to the Brain start to form endogenous Ab plaques until 15 mo of age, providing a wide time window The infectivity of PrP seeds commonly involves within which to observe the spread of lesions their translocation from the periphery to the following focal seeding in the hippocampus. brain (Aguzzi 2003). Tostudy whether Ab seeds R1.40 mice were injected intracerebrally with delivered to peripheral sites can stimulate the Ab seeds at 3 mo of age, and by 15 mo, much formation of Ab plaques or CAA in the brain, of the brain was beset by Ab deposits (Hama- APP transgenic mice were inoculated via vari- guchi et al. 2012). Analysis of seeded R1.40 mice ous routes. In a first report, the oral, intranasal, and APPPS1 mice at different time points sup- and intravenous delivery of Ab seeds failed to ports the hypothesis that the infusion of exoge- induce significant plaque formation in the nous seeds into the hippocampus elicits the brain, at least within the incubation period spread of lesions along axonal routes; specific- examined (Eisele et al. 2009). However, in sub- ally, Ab deposits appear in structures of the sequent studies using a slightly prolonged incu- limbic connectome and subsequently in regions bation time, the injection of aggregated Ab-rich that are increasingly distant from the initial site brain extracts into the peritoneal cavity induced of injection (Fig. 3) (Ye et al. 2015b). A similar significant cerebral Ab-amyloidosis, particular- www.perspectivesinmedicine.org systematic emergence of endogenous Ab lesions ly in the cerebral vasculature (Eisele et al. 2010, has been reported in an APP-transgenic mouse 2014). The magnitude of the seeding effect cor- model expressing Arctic mutant Ab (Ro¨nnba¨ck related with the amount of intraperitoneally in- et al. 2012). oculated Ab seeds and with the expression of These findings suggest that Ab aggregates APP/Ab in the brain (but not in the periphery). traffic along neuronal pathways, but whether The pattern of immunoreactive lesions in this this occurs by constrained diffusion along fiber model suggests that the Ab seeds enter the brain pathways or by active uptake and transport by at multiple sites (Eisele et al. 2014). Thus, Ab has not yet been determined in vivo. In seeds, like PrP prions, can reach the brain from addition, the role of the transgene promoter in outside the central (CNS). How defining the regional emergence of lesions re- they do this remains uncertain; transport by mainsto be fully defined. However, invitro stud- macrophages through the bloodstream is one ies have shown that cultured neurons can take up possibility (Eisele et al. 2014; Cintron et al. and transport multimeric Ab (Nath et al. 2012; 2015), but alternative routes of conveyance Domert et al. 2014; Song et al. 2014). In addi- (such as neuronal transport) could also be in- tion, it is important to consider the possibility volved.

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Prion-Like Properties of Aggregated Ab

EVIDENCE FOR THE PRION-LIKE SEEDING suggest that AD can be transmitted from per- OF Ab IN son to person under ordinary circumstances. Rather, current evidence indicates that AD be- From the late 1950s until 1985, a number of gins endogenously with the misfolding, cor- children with conditions such as short stature ruptive templating, and self-assembly of Ab were treated with growth hormone that had (Jucker and Walker 2013). As noted above, been isolated from cadaveric human pituitary the risk of AD is increased by mutations and glands. Much later it was discovered that some polymorphisms that promote Ab misfolding batches of the hormone were contaminated and aggregation. Whether and how physiolog- with PrP prions, resulting in iatrogenic Creutz- ical and environmental factors influence the feldt–Jakob disease (CJD) in a subset of pa- Ab cascade and how the aggregation of Ab is tients (Rudge et al. 2015). Recently, eight ultimately linked to dementia remain open hormone recipients in Great Britain who died questions, but it now seems likely that Ab ag- of CJD at ages ranging from 36 to 51 yr were gregation is a central mechanism on which risk examined for the co-presence of AD-type le- factors converge to facilitate the development sions. Four of them had significant Ab accu- of AD. mulation in the form of Ab plaques and CAA, and two others had sparse Ab deposits (Jaun- CONCLUSIONS: THE PRION PARADIGM, muktane et al. 2015). These findings raise the Ab, AND AD possibility that some batches of growth hor- mone were contaminated with Ab seeds that Considerable research now supports the conclu- originated from pituitary glands collected sion that Ab can be induced to aggregate and from patients who had died with AD (or incip- spread in the brain by a prion-like mechanism. ient AD) (Jucker and Walker 2015). Because AD involves a clinically silent period of intrace- the growth hormone recipients had died of rebral that precedes demen- CJD, it is unknown whether they ultimately tia by decades (Jack et al. 2010; Holtzman et al. would have developed AD (none of them dis- 2011; Selkoe 2011; Bateman et al. 2012). In this played signs of tauopathy). It will be informa- light, the seeding model of Ab deposition sub- tive to follow the surviving recipients who did stantiates a primary role for Ab aggregation in not manifest CJD to assess their relative risk of the early stages of AD and reinforces the logic of AD and other neurodegenerative proteo- therapeutically targeting Ab seeds (Jucker and pathies. A preliminary analysis in the United Walker 2011), preferably early in the pathogenic States suggests that growth hormone recipients cascade. www.perspectivesinmedicine.org may not be more likely to develop AD (Irwin In Table 1, we summarize the features of Ab et al. 2013), although a very long incubation seeds that justify their inclusion within the wid- period is likely. Also important will be to ex- ening context of the prion concept. Fully devel- amine any remaining batches of cadaveric oped AD has not yet been induced in any animal growth hormone for the presence of Ab and model; indeed, AD appears to be unique to hu- other types of prion-like seeds. Very recently, mans (Walker and Cork 1999; Jucker 2010; He- CJD patients who had received PrP prion–con- uer et al. 2012). In addition, there is no defini- taminated dura mater transplants many years tive evidence to date that AD per se can be earlier were also found to have significantly transmitted to humans by infection with exog- increased Ab plaques and CAA (Frontzek enous Ab seeds. However, the exogenous seed- et al. 2016). ing model provides compelling evidence for a These studies have furnished the first evi- molecular mechanism by which Ab seeds act to dence that the aggregation of a protein other instigate and perpetuate AD pathology. Present than PrP can be instigated in the human brain knowledge favors a pathogenic model in which by exogenous seeds, but in neither case was AD originates from the endogenous generation full-blown AD induced, nor do the findings of Ab seeds. For these reasons, and because

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Table 1. Comparison of PrP prions and Ab seeds REFERENCES b PrP A Aguzzi A. 2003. Prions and the immune system: A journey Properties prions seeds through gut, spleen, and nerves. Adv Immunol 81: 123– Structure 171. b-sheet-enriched conformation Yes Yes Aguzzi A, Heikenwalder M, Polymenidou M. 2007. Insights into prion strains and . Nat Rev Mol Biol Aggregation Yes Yes 8: 552–561. Seeding capacity Alzheimer A. 1906. U¨ ber einen eigenartigen schweren Seeds initiate pathology Yes Yes Erkrankungsprozeß der Hirnrinde. Neurologisches Cen- Purified and synthetic materials Ye s Ye s tralblatt 23: 1129–1136. seed Appel T, Wolff M, von Rheinbaben F, Heinzel M, Riesner D. 2001. Heat stability of prion rods and recombinant prion Seeds instigate de novo Ye s Ye s protein in water, and lipid–water mixtures. J Gen deposition Virol 82: 465–473. Strain variation Arnold SE, Hyman BT, Flory J, Damasio AR, Van Hoesen Existence of different strains Yes Yes GW. 1991. The topographical and neuroanatomical dis- tribution of neurofibrillary tangles and neuritic plaques Stability in the cerebral cortex of patients with Alzheimer’s disease. Differential resistance to PK Ye s Ye s Cereb Cortex 1: 103–116. digestion Arszovszki A, Borhegyi Z, Klausberger T.2014. Three axonal projection routes of individual pyramidal cells in the Resistance to high temperature Yes Yes ventral CA1 hippocampus. Front Neuroanat 8: 53. Resistance to formaldehyde Ye s Ye s Baker HF, Ridley RM, Duchen LW, Crow TJ, Bruton CJ. fixation 1993. Evidence for the experimental transmission of ce- Trafficking rebral b-amyloidosis to primates. Int J Exp Pathol 74: 441–454. Spreading within and to the Ye s Ye s Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, brain Fox NC, Marcus DS, Cairns NJ, Xie X, Blazey TM, et al. Infectivity 2012. Clinical and biomarker changes in dominantly in- Serial transmissibility in mice Yes Yes herited Alzheimer’s disease. N Engl J Med 367: 795–804. Transmissibility to humans Yes (Yes)a Benilova I, Gallardo R, Ungureanu AA, Castillo Cano V, Snellinx A, Ramakers M, Bartic C, Rousseau F,Schymko- PK, Proteinase K. witz J, De Strooper B. 2014. The Alzheimer disease aProbable transmission of Ab deposition. protective mutation A2Tmodulates kinetic and thermo- dynamic properties of amyloid-b (Ab) aggregation. J Biol Chem 289: 30977–30989. the term “prion” is now widely used to refer to Bero AW,YanP,Roh JH, Cirrito JR, Stewart FR, Raichle ME, proteinaceous agents of biological information Lee JM, Holtzman DM. 2011. Neuronal activity regulates the regional vulnerability to amyloid-b deposition. Nat transfer in both health and disease, we suggest Neurosci 14: 750–756.

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Prion-Like Properties of Aggregated Ab

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The Prion-Like Properties of Amyloid-β Assemblies: Implications for Alzheimer's Disease

Lary C. Walker, Juliane Schelle and

Cold Spring Harb Perspect Med 2016; doi: 10.1101/cshperspect.a024398 originally published online June 7, 2016

Subject Collection Prion Diseases

TDP-43 Prions and Pathophysiology of α-Synuclein Takashi Nonaka and Masato Hasegawa Jacqueline Burré, Manu Sharma and Thomas C. Südhof α-Synuclein: Prions Molecular Mechanisms of Chronic Wasting Amanda L. Woerman, Joel C. Watts, Atsushi Disease Prion Propagation Aoyagi, et al. Julie A. Moreno and Glenn C. Telling Genetics of Synucleinopathies Genetics of Amyotrophic Lateral Sclerosis Robert L. Nussbaum Mehdi Ghasemi and Robert H. Brown, Jr. β-Amyloid Prions and the Pathobiology of The Genetics of C9orf72 Expansions Alzheimer's Disease Ilse Gijselinck, Marc Cruts and Christine Van Joel C. Watts and Stanley B. Prusiner Broeckhoven Disease Mechanisms of C9ORF72 Repeat Prion-Like Characteristics of Expansions Polyglutamine-Containing Proteins Tania F. Gendron and Leonard Petrucelli Margaret M.P. Pearce and Ron R. Kopito Chronic Traumatic Encephalopathy: Is Latency in Therapeutic Strategies for Restoring Tau Symptom Onset Explained by Tau Propagation? Homeostasis Joshua Kriegel, Zachary Papadopoulos and Ann C. Zapporah T. Young, Sue Ann Mok and Jason E. McKee Gestwicki Noncerebral Amyloidoses: Aspects on Seeding, Fused in Sarcoma Neuropathology in Cross-Seeding, and Transmission Neurodegenerative Disease Gunilla T. Westermark, Marcus Fändrich, Ian R.A. Mackenzie and Manuela Neumann Katarzyna Lundmark, et al. Structural and Chemical Biology of Presenilin Experimental Models of Inherited PrP Prion Complexes Diseases Douglas S. Johnson, Yue-Ming Li, Martin Joel C. Watts and Stanley B. Prusiner Pettersson, et al.

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