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. 2016 Jul;6(7):a024398. doi: 10.1101/cshperspect.a024398

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

Lary C Walker 1, Juliane Schelle 2,3, Mathias Jucker 2,3
PMCID: PMC4930920  PMID: 27270558

Abstract

Since the discovery that prion diseases can be transmitted to experimental animals by inoculation with afflicted brain matter, researchers have speculated that the brains 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 dementia 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 protein fragment amyloid-β (Aβ). At the molecular level, this mechanism of nucleated protein self-assembly is virtually identical to that of prions consisting of the prion protein (PrP). The formation, propagation, and spread of Aβ seeds within the brain can thus be considered a fundamental feature of AD pathogenesis.

Brain plaques composed of amyloid-β (Aβ) protein fragments are one of the hallmark features of Alzheimer’s disease. Aβ appears to aggregate and spread in the brain much like prions do.

Alzheimer’s disease (AD) is the most frequent cause of dementia and a growing social, medical, and economic challenge to societies in which the elderly population is rapidly growing (Dartigues 2009; Holtzman et al. 2011; Reitz et al. 2011). The involvement of abnormal proteins in AD has been evident since Alois Alzheimer’s original histopathological descriptions of the disease in the early 20th century (Alzheimer 1906). Even today, a conclusive diagnosis of AD in a patient with dementia requires the significant presence of two cardinal brain lesions at autopsy: amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs) (Fig. 1). The defining components of plaques are extracellular collections of aggregated Aβ protein, whereas NFTs consist of intracellular bundles of hyperphosphorylated tau protein (Duyckaerts et al. 2009; Holtzman et al. 2011). In both cases, the proteins that accumulate assume a tertiary structure (or fold) that is unusually rich in β-sheet, which in turn promotes the structural corruption and self-assembly of like molecules into small oligomeric and larger fibrillar assemblies with neurotoxic properties (Haass and Selkoe 2007; Klein 2013). The resulting aggregates have features that are often characteristic of amyloid (Eisenberg and Jucker 2012). Although the presence of amyloid signifies a proteopathic process, amyloid per se is not always required for the complete manifestation of disease. Both Aβ plaques (Fig. 2) and tau lesions can be modeled in transgenic mice (Jucker 2010). With the progression of AD, Aβ deposition and NFTs increase in number and affect large areas of the brain in a characteristic and brain region–specific manner (Braak and Braak 1991; Thal et al. 2002; Jucker and Walker 2013). In addition to these pathological hallmarks and diagnostic lesions, the AD brain is typified by impaired synaptic function, neuroinflammation, and neuronal loss, which ultimately contribute to the full expression of dementia (Holtzman et al. 2011; Nelson et al. 2012).

Figure 1.

Figure 1.

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The canonical histopathology of Alzheimer’s disease (AD). Amyloid-β (Aβ) plaques consist of extracellular deposits of Aβ (brown; detected by immunostaining with a polyclonal antibody to Aβ), and neurofibrillary tangles (NFTs) consist of intracellular masses of ectopic tau protein (purple; detected by immunostaining with a monoclonal antibody to tau). Scale bar, 100 µm.

Figure 2.

Figure 2.

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

In addition to plaques, Aβ accumulates to a variable extent in the walls of cerebral blood vessels in AD patients; this cerebral amyloid angiopathy (CAA) of the Aβ-type, although not pathognomonic for AD, is a risk factor for hemorrhagic stroke (Yamada 2013) and can independently contribute to cognitive decline (Biffi and Greenberg 2011; Reijmer et al. 2015). Moreover, in most cases of AD (particularly in older patients), typical pathological features are accompanied by variable amounts of comorbid lesions, such as vascular abnormalities and/or aggregates of other, non-AD-specific pathogenic proteins such as α-synuclein, TDP-43, and others (Neuropathology Group, Medical Research Council Cognitive Function and Aging Study 2001; Knopman et al. 2003; Schneider et al. 2007; Nelson et al. 2012).

THE PRIMACY OF Aβ IN THE AD PATHOGENIC CASCADE

Although the degree of tauopathy correlates more strongly with cognitive decline than does the buildup of Aβ (Giannakopoulos et al. 2003), extant evidence indicates that in AD (Hardy and Selkoe 2002; Holtzman et al. 2011; Nelson et al. 2012) and in genetically modified mice (Götz et al. 2001; Lewis et al. 2001; Bolmont et al. 2007; Héraud et al. 2014; Stancu et al. 2014; Vasconcelos et al. 2016), tauopathy is downstream from Aβ proteopathy. Moreover, the genetic causes of autosomal dominant AD identified so far all affect Aβ by enhancing its release from the Aβ-precursor protein (APP) or its tendency to self-aggregate (Hardy and Selkoe 2002). In contrast, a rare mutation in the APP gene that causes an amino acid substitution at position 2 of Aβ (A673T according to APP770 numbering) reduces the production of Aβ following β-secretase cleavage (Jonsson et al. 2012) and also lowers the propensity of Aβ to aggregate (Benilova et al. 2014); the A673T mutation thereby also lessens the risk of developing AD (Jonsson et al. 2012). Substitution of valine for alanine at this site (A673V) enhances the production and aggregation of Aβ and causes an autosomal recessive form of AD (Di Fede et al. 2009). Furthermore, assessment of biomarkers in subjects with autosomal dominant causative mutations and in subjects with idiopathic AD before the likely age of dementia onset shows that Aβ changes in the brain are the first harbinger of impending disease, and that this can occur decades before clinical dementia sets in (Jack et al. 2010; Holtzman et al. 2011; Selkoe 2011; Bateman et al. 2012). These findings together highlight the pivotal role of Aβ in the pathogenesis of AD.

EXPERIMENTAL EVIDENCE FOR THE PRION-LIKE SEEDING OF Aβ AGGREGATION

Since the discovery that prion diseases can be transmitted to experimental animals by inoculation with afflicted brain fractions, researchers have speculated that the brains of patients suffering from other neurodegenerative diseases might also harbor causative agents with transmissible properties (Prusiner 1984; Gajdusek 1994). A team in Great Britain reported that Aβ load is increased in the brains of nonhuman primates by the intracerebral injection of AD brain homogenates (Baker et al. 1993). However, the experiments required an incubation period of >5 yr, and the causative agent and mechanism of action remained uncertain. In the late 1990s, as the first transgenic mouse models of cerebral β-amyloidosis became available (Games et al. 1995; Hsiao et al. 1996; Sturchler-Pierrat et al. 1997), we set out to definitively test the hypothesis that the prion paradigm of nucleated protein self-assembly also applies to Aβ. This series of studies, in conjunction with investigations in other laboratories, now provides support for the concept that the molecular properties of pathogenic Aβ assemblies are virtually identical to those of prion protein (PrP) prions (Walker and Jucker 2015).

In our first experiments, extracts of autopsy-derived brain samples from AD patients and controls were injected stereotaxically into the hippocampal formation and/or neocortex of young, predepositing APP-transgenic mice (Kane et al. 2000; Walker et al. 2002; Meyer-Luehmann et al. 2006). After incubation periods ranging from a few hours to 12 mo, the brains were analyzed immunohistochemically. Because only small amounts of extract were injected (typically 1–2.5 µL, containing ∼10 ng Aβ/μL), little or no immunohistochemically detectable Aβ remained after a few days or more of incubation. However, by 3 to 5 mo postsurgery, at a point when the transgenic mice had not yet begun to form endogenous Aβ plaques and CAA, Aβ deposits emerged and increased dramatically with longer incubation intervals (Fig. 3).

Figure 3.

Figure 3.

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

The degree of Aβ-seeding in mice is directly proportional to the concentration of the brain extract (Meyer-Luehmann et al. 2006; Fritschi et al. 2014b). Seeded Aβ deposits are both diffuse and congophilic, and dense-core (congophilic) plaques are associated with cellular reactivity that includes microgliosis, astrocytosis, and abnormal neurites containing increased APP and hyperphosphorylated tau. Importantly, no Aβ deposits emerged in nontransgenic host mice, and brain extracts from non-AD control donors that lacked Aβ deposition did not induce significant Aβ lesions (Kane et al. 2000; Meyer-Luehmann et al. 2006). NFTs per se have not been detected in seeded APP-transgenic mouse models and would likely require the expression of human-sequence tau in host mice (Bolmont et al. 2007).

These findings indicate that Aβ seeding requires both a donor brain extract that contains Aβ seeds and a host that is capable of generating Aβ plaques and/or CAA of the Aβ type. Because injections of control brain extracts failed to seed plaque formation, these findings also mitigate against the possibility that the induction of Aβ deposition is simply caused by brain injury. The concern that the seeding effect might result from factors in the human brain that indirectly stimulate Aβ aggregation, such as a human-specific virus or an immune response to the foreign brain fractions, was ruled out by a robust seeding response to Aβ-rich brain extracts from aged APP transgenic donor mice of the same strain as the host mice (Meyer-Luehmann et al. 2006; Watts et al. 2011).

The next step was to define the nature of the Aβ seeds. Denaturation of brain extracts with formic acid (Meyer-Luehmann et al. 2006), or the specific depletion of Aβ by antibodies or reagents that bind and remove amyloid proteins from the extract, abrogated the seeding effect (Meyer-Luehmann et al. 2006; Duran-Aniotz et al. 2014). Seeding was also blocked when the extract was mixed with an Aβ antibody and then injected into the brain (Meyer-Luehmann et al. 2006).

These results confirmed that Aβ is essential to the seeding capacity of brain extracts, but they left open the question of whether pure, aggregated, synthetic Aβ is able to induce deposition in mice. In early experiments, the injection of various amounts of synthetic Aβ fibrils did not cause obvious induction of new plaques up to 5 mo postinjection (Meyer-Luehmann et al. 2006). This finding was not entirely unexpected, given the poor potency of recombinant PrP in inducing brain disease (Legname et al. 2004). More recently, however, it was shown that with a larger dose of aggregated Aβ and a longer incubation time, Aβ deposition can be instigated by multimeric, synthetic Aβ (Stöhr et al. 2012). Aβ seeds, then, like PrP prions, gain considerable potency when formed within the brain. The seeded conversion of synthetic Aβ into potent, in vivo–active Aβ seeds has recently been achieved in a hippocampal slice culture model (Novotny et al. 2016). Further deciphering of the factors responsible for the conversion will be important to understanding the pathogenicity of multimeric Aβ in AD. For instance, the addition of certain cofactors to the medium in which synthetic PrP is aggregated augments the seeding potential of synthetic PrP prions (Wang et al. 2010; Deleault et al. 2012; Zhang et al. 2014). It will be informative to determine whether cofactors might also increase the potency of synthetic Aβ seeds.

THE INTERACTION OF Aβ STRAINS AND HOST FACTORS

To induce Aβ deposition in the in vivo seeding model, it is necessary for the host animal to express seeding-capable Aβ (Kane et al. 2000; Meyer-Luehmann et al. 2006; Morales et al. 2012; Rosen et al. 2012). In earlier studies, transgenic mouse models that eventually develop endogenous Aβ lesions as they age were used. Prion disease, however, is induced de novo by infection with PrP prions in animals that otherwise would never have manifested the disease. To determine whether Aβ deposits can also be generated de novo in relatively resistant animals, Aβ-seeding experiments were undertaken in APP-transgenic mice (Morales et al. 2012) and rats (Rosen et al. 2012) that do not generate plaques or CAA within their normal life spans. In both instances, Aβ deposition was induced in the brain after a suitable incubation period.

The existence of variant structural strains of Aβ is increasingly well established (Eisenberg and Jucker 2012; Lu et al. 2013; Hatami et al. 2014; Spirig et al. 2014; Cohen et al. 2015). Growing evidence supports the hypothesis that Aβ seeds, like PrP prions (Aguzzi et al. 2007; Collinge and Clarke 2007; Prusiner 2013), can also adopt different molecular conformations that are linked to their functionality in vivo (Meyer-Luehmann et al. 2006; Eisenberg and Jucker 2012; Stöhr et al. 2014; Watts et al. 2014). APP-transgenic mice (APP23 mice) and transgenic mice expressing human APP along with human presenilin-1 (APPPS1 mice) develop parenchymal Aβ deposits that differ morphologically at the light-microscopic level (Heilbronner et al. 2013). When Aβ-laden brain extract from one model was injected intracerebrally into the other model, the lesion morphologies, as revealed by immunohistochemistry, and the molecular architecture of the deposited Aβ, as assessed by amyloid conformation-sensitive oligothiophene dyes, showed characteristics of both the host and seeding extract (Heilbronner et al. 2013). Interestingly, the ratio of Aβ40 to Aβ42 in the induced Aβ deposits in host mice also was influenced by exogenous seeds, suggesting that this ratio may contribute to the strain-like properties of Aβ assemblies (Heilbronner et al. 2013). Transmission studies have found that brain extracts from AD patients carrying either the Swedish or Arctic mutation injected into the brains of susceptible mice induced distinct Aβ pathologies that could be serially propagated and maintained after multiple passages (Watts et al. 2014). Finally, in a given host model, if seeds are infused into brain regions other than the hippocampus, the deposits that emerge are often typical of the morphotypes displayed by the endogenous (unseeded) lesions that form in the respective structures as the mice age (Eisele et al. 2009). Hence, not only the host mouse but also the local brain conditions influence the types of lesions that are induced by exogenous Aβ seeds.

THE SIZE AND POTENCY OF Aβ SEEDS

Prions exist in a range of sizes, and the most potent PrP prions appear to be small, soluble species (Silveira et al. 2005). To assess the size range of Aβ seeds, brain extracts were subjected to ultracentrifugation (100,000×g for 1 h). Most (>99%) of the Aβ from the extract sediments in the pellet, which, when injected intracerebrally into mice, seeds Aβ aggregation almost as effectively as does the original brain extract. Surprisingly, however, soluble Aβ in the high-speed supernatant seeded ∼30% as much histochemically detectable Aβ deposition as did the insoluble pellet, although <1% of the Aβ was in the soluble fraction. Therefore, small, soluble Aβ assemblies, like small PrP prions, are highly effective seeds. Given their limited dimensions, it is conceivable that soluble Aβ seeds traffic through the brain more readily than do larger fibrils. Interestingly, these soluble seeds, unlike insoluble multimers, are quite sensitive to destruction by proteinase K (PK), suggesting that they may be particularly susceptible to therapeutic intervention (Langer et al. 2011).

To assess the potency of Aβ seeds in stimulating cerebral Aβ-deposition, serially diluted brain extracts from autopsied AD patients were injected into the hippocampus of young, APP-transgenic host mice. The degree of induction diminished with increasing dilution, but even subattomolar levels of brain-derived Aβ were found to stimulate Aβ-proteopathy in the hosts (Fritschi et al. 2014b). In a recent experiment, Aβ seed–rich brain extracts were injected into APP-null host mice that, because of the absence of Aβ, are incapable of replicating Aβ seeds; 6 mo later, brain extracts from these APP-null mice were still able to seed Aβ deposition in APP-transgenic hosts, indicative of extraordinary potency and robustness of Aβ seeds (Ye et al. 2015a). Surprisingly, Aβ in the cerebrospinal fluid (CSF) of AD patients and aged APP-transgenic donor mice was devoid of significant in vivo seeding activity, even at levels of Aβ exceeding those in the most concentrated brain extracts (Fritschi et al. 2014b). The reasons for the inability of Aβ in the CSF to seed in vivo remain uncertain, but the mechanism could reveal a novel means of impeding the seeding cascade in the brain.

THE ROBUSTNESS OF Aβ SEEDS

Although PrP prions vary in their stability (Tzaban et al. 2002; Choi et al. 2010; Zou et al. 2010; Gambetti et al. 2011), a notable characteristic of infectious prions is that some of them are quite durable, even under harsh environmental conditions (Appel et al. 2001; Wiggins 2009). The ability of these prions to retain their pathogenic properties contributes to their infectivity, including rare instances of infection in neurosurgical patients exposed to PrP prion–contaminated surgical instruments that had been sterilized via conventional methods (Brown et al. 2012; Thomas et al. 2013). Studies in experimental animals confirm the persistent infectivity of PrP prions bound to stainless-steel wire (Flechsig et al. 2001), even after the wire has been exposed to formaldehyde (Zobeley et al. 1999).

A first hint that Aβ seeds are also durable agents came from studies in which Aβ-rich brain extract was boiled for 5 min and still retained its seeding capacity (Meyer-Luehmann et al. 2006). In later studies drawing from work in the PrP prion field, a minute quantity of Aβ-rich brain extract was dried onto stainless-steel wires, and the wires were implanted in the brains of APP-transgenic host mice (Eisele et al. 2009). After an incubation period of 4 mo, Aβ lesions were induced in the region immediately surrounding the wire and, to a lesser extent, in more distant areas. Plasma sterilization of the contaminated wires before implantation prevented plaque induction, but heating them for 10 min at 95°C did not (Eisele et al. 2009). Although this study suggests that Aβ seeds on insufficiently sterilized surgical instruments might increase the risk of AD, presently this is only a theoretical possibility.

One of the first clues that the agent that transmits PrP prion disease is highly unorthodox surfaced unexpectedly in the 1930s when William Gordon immunized sheep against a viral illness called louping-ill (Gordon 1946). The vaccine was prepared from formaldehyde-fixed nervous tissue derived from sheep that had been sick with louping-ill. Although the vaccine worked well to reduce the incidence of louping-ill, after several years the vaccinated sheep began to develop scrapie. Gordon surmised that some of the sheep used to prepare the vaccine were also incubating the scrapie agent and that the agent is resistant to inactivation by formaldehyde (Gordon 1946). This conclusion has been supported by subsequent research (Pattison 1965; Brown et al. 1990).

To determine whether Aβ seeds are similarly resistant to formaldehyde inactivation, formaldehyde-fixed brain samples from AD patients and APP-transgenic mice were injected into APP-transgenic hosts. The fixed brain samples retained their seeding potential, even after as long as 2 yr in formaldehyde (Fritschi et al. 2014a). Additionally, the spectral patterns of luminescent conjugated oligothiophenes bound to Aβ indicated that the molecular architecture of the Aβ seeds was maintained in fixed tissue and could be faithfully transmitted to the host mice (Fritschi et al. 2014a).

TRAFFICKING OF Aβ SEEDS

Trafficking within the Brain

PrP prion–laden extracts injected into the brains of transgenic mice yield pathology that is not restricted to the injection site; rather, the PrP prions propagate and spread throughout most of the brain (Fraser 1982; Buyukmihci et al. 1983; Kimberlin and Walker 1986; Liberski et al. 2012; Rangel et al. 2014). In the case of AD, the neuroanatomical distribution of plaques and tangles at different disease stages suggests that the lesions propagate among axonally connected brain areas (Saper et al. 1987; Arnold et al. 1991; Braak and Braak 1995), a possibility that is garnering support from contemporary imaging modalities (Bero et al. 2011; Zhou et al. 2012; Iturria-Medina et al. 2014; Raj et al. 2015). Experimentally, within 24 h of injecting Aβ-rich brain extract into the hippocampus, immunohistochemical examination shows that the extract diffuses away from the injection site and tends to concentrate along the hippocampal fissure, around blood vessels, and in the subpial zone, regions that exhibit a strong seeding response following a much longer incubation period (Walker et al. 2002; Ye et al. 2015b). The injected Aβ rapidly becomes undetectable histochemically, and a lag period ensues before the focal emergence of induced deposits in the injected hippocampus, usually after a month or more depending on the mouse model (Kane et al. 2000; Meyer-Luehmann et al. 2006; Eisele et al. 2014). Over time, Aβ deposits then begin to appear in other brain regions, most notably in the entorhinal cortex ventrolateral to the dorsal hippocampal injection site (Walker et al. 2002; Meyer-Luehmann et al. 2006; Eisele et al. 2009). When the seeds are placed in the entorhinal cortex, the earliest secondary deposits emerge selectively in the hippocampal formation (Eisele et al. 2009). Because the entorhinal cortex is a major source of neocortical communication with the hippocampal formation (Suh et al. 2011; Arszovszki et al. 2014), these studies provided the first clues that neuronal pathways might define the spread of Aβ pathology through the brain.

To further test the hypothesis that Aβ seeds propagate by sequential seeding requires extending the incubation period into the age when most transgenic mouse models begin to generate deposits on their own. For this purpose, the R1.40 APP-transgenic mouse model (Lamb et al. 1997) was used. These mice do not start to form endogenous Aβ plaques until 15 mo of age, providing a wide time window within which to observe the spread of lesions following focal seeding in the hippocampus. R1.40 mice were injected intracerebrally with Aβ seeds at 3 mo of age, and by 15 mo, much of the brain was beset by Aβ deposits (Hamaguchi et al. 2012). Analysis of seeded R1.40 mice and APPPS1 mice at different time points supports the hypothesis that the infusion of exogenous seeds into the hippocampus elicits the spread of lesions along axonal routes; specifically, Aβ deposits appear in structures of the limbic connectome and subsequently in regions that are increasingly distant from the initial site of injection (Fig. 3) (Ye et al. 2015b). A similar systematic emergence of endogenous Aβ lesions has been reported in an APP-transgenic mouse model expressing Arctic mutant Aβ (Rönnbäck et al. 2012).

These findings suggest that Aβ aggregates traffic along neuronal pathways, but whether this occurs by constrained diffusion along fiber pathways or by active uptake and transport by neurons has not yet been determined in vivo. In addition, the role of the transgene promoter in defining the regional emergence of lesions remains to be fully defined. However, in vitro studies have shown that cultured neurons can take up and transport multimeric Aβ (Nath et al. 2012; Domert et al. 2014; Song et al. 2014). In addition, it is important to consider the possibility that exogenous Aβ seeds (and their endogenous descendants) can translocate by other means. In mice seeded intrahippocampally with Aβ-rich brain extracts, we have noted the premature appearance of CAA in the thalamus (Meyer-Luehmann et al. 2006). How thalamic CAA is stimulated in hippocampally seeded mice remains unknown. In this light, alternative modes of seed trafficking, beyond passive diffusion and neuronal transport, should be considered. These include perivascular and paravascular flow (Weller et al. 1998; Thal et al. 2007; Iliff et al. 2012) or uptake and transport by nonneuronal cells such as macrophages (Eisele et al. 2009) (see below).

Trafficking from the Periphery to the Brain

The infectivity of PrP seeds commonly involves their translocation from the periphery to the brain (Aguzzi 2003). To study whether Aβ seeds delivered to peripheral sites can stimulate the formation of Aβ plaques or CAA in the brain, APP transgenic mice were inoculated via various routes. In a first report, the oral, intranasal, and intravenous delivery of Aβ seeds failed to induce significant plaque formation in the brain, at least within the incubation period examined (Eisele et al. 2009). However, in subsequent studies using a slightly prolonged incubation time, the injection of aggregated Aβ-rich brain extracts into the peritoneal cavity induced significant cerebral Aβ-amyloidosis, particularly in the cerebral vasculature (Eisele et al. 2010, 2014). The magnitude of the seeding effect correlated with the amount of intraperitoneally inoculated Aβ seeds and with the expression of APP/Aβ in the brain (but not in the periphery). The pattern of immunoreactive lesions in this model suggests that the Aβ seeds enter the brain at multiple sites (Eisele et al. 2014). Thus, Aβ seeds, like PrP prions, can reach the brain from outside the central nervous system (CNS). How they do this remains uncertain; transport by macrophages through the bloodstream is one possibility (Eisele et al. 2014; Cintron et al. 2015), but alternative routes of conveyance (such as neuronal transport) could also be involved.

EVIDENCE FOR THE PRION-LIKE SEEDING OF Aβ IN HUMANS

From the late 1950s until 1985, a number of children with conditions such as short stature were treated with growth hormone that had been isolated from cadaveric human pituitary glands. Much later it was discovered that some batches of the hormone were contaminated with PrP prions, resulting in iatrogenic Creutzfeldt–Jakob disease (CJD) in a subset of patients (Rudge et al. 2015). Recently, eight hormone recipients in Great Britain who died of CJD at ages ranging from 36 to 51 yr were examined for the co-presence of AD-type lesions. Four of them had significant Aβ accumulation in the form of Aβ plaques and CAA, and two others had sparse Aβ deposits (Jaunmuktane et al. 2015). These findings raise the possibility that some batches of growth hormone were contaminated with Aβ seeds that originated from pituitary glands collected from patients who had died with AD (or incipient AD) (Jucker and Walker 2015). Because the growth hormone recipients had died of CJD, it is unknown whether they ultimately would have developed AD (none of them displayed signs of tauopathy). It will be informative to follow the surviving recipients who did not manifest CJD to assess their relative risk of AD and other neurodegenerative proteopathies. A preliminary analysis in the United States suggests that growth hormone recipients may not be more likely to develop AD (Irwin et al. 2013), although a very long incubation period is likely. Also important will be to examine any remaining batches of cadaveric growth hormone for the presence of Aβ and other types of prion-like seeds. Very recently, CJD patients who had received PrP prion–contaminated dura mater transplants many years earlier were also found to have significantly increased Aβ plaques and CAA (Frontzek et al. 2016).

These studies have furnished the first evidence that the aggregation of a protein other than PrP can be instigated in the human brain by exogenous seeds, but in neither case was full-blown AD induced, nor do the findings suggest that AD can be transmitted from person to person under ordinary circumstances. Rather, current evidence indicates that AD begins endogenously with the misfolding, corruptive templating, and self-assembly of Aβ (Jucker and Walker 2013). As noted above, the risk of AD is increased by mutations and polymorphisms that promote Aβ misfolding and aggregation. Whether and how physiological and environmental factors influence the Aβ cascade and how the aggregation of Aβ is ultimately linked to dementia remain open questions, but it now seems likely that Aβ aggregation is a central mechanism on which risk factors converge to facilitate the development of AD.

CONCLUSIONS: THE PRION PARADIGM, Aβ, AND AD

Considerable research now supports the conclusion that Aβ can be induced to aggregate and spread in the brain by a prion-like mechanism. AD involves a clinically silent period of intracerebral protein aggregation that precedes dementia by decades (Jack et al. 2010; Holtzman et al. 2011; Selkoe 2011; Bateman et al. 2012). In this light, the seeding model of Aβ deposition substantiates a primary role for Aβ aggregation in the early stages of AD and reinforces the logic of therapeutically targeting Aβ seeds (Jucker and Walker 2011), preferably early in the pathogenic cascade.

In Table 1, we summarize the features of Aβ seeds that justify their inclusion within the widening context of the prion concept. Fully developed AD has not yet been induced in any animal model; indeed, AD appears to be unique to humans (Walker and Cork 1999; Jucker 2010; Heuer et al. 2012). In addition, there is no definitive evidence to date that AD per se can be transmitted to humans by infection with exogenous Aβ seeds. However, the exogenous seeding model provides compelling evidence for a molecular mechanism by which Aβ seeds act to instigate and perpetuate AD pathology. Present knowledge favors a pathogenic model in which AD originates from the endogenous generation of Aβ seeds. For these reasons, and because the term “prion” is now widely used to refer to proteinaceous agents of biological information transfer in both health and disease, we suggest that the power of the prion concept can be enhanced by defining prions as “proteinaceous nucleating particles” (Walker and Jucker 2015). In light of this more comprehensive definition, research now supports the designation of Aβ seeds as Aβ prions. Defining prions according to their molecular properties has the additional advantage of mitigating unwarranted concern about the transmissibility of noninfectious proteopathies.

Table 1.

Comparison of PrP prions and Aβ seeds

Properties PrP prions Aβ seeds
Structure
β-sheet-enriched conformation Yes Yes
Aggregation Yes Yes
Seeding capacity
Seeds initiate pathology Yes Yes
Purified and synthetic materials seed Yes Yes
Seeds instigate de novo deposition Yes Yes
Strain variation
Existence of different strains Yes Yes
Stability
Differential resistance to PK digestion Yes Yes
Resistance to high temperature Yes Yes
Resistance to formaldehyde fixation Yes Yes
Trafficking
Spreading within and to the brain Yes Yes
Infectivity
Serial transmissibility in mice Yes Yes
Transmissibility to humans Yes (Yes)a
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PK, Proteinase K.

aProbable transmission of Aβ deposition.

ACKNOWLEDGMENTS

We thank Sarah Fritschi and Ulrike Obermüller for their help in preparing this review and Simone Eberle for editorial assistance.

Footnotes

Editor: Stanley B. Prusiner

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

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