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

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The Prion-Like Properties of Amyloid-Β Assemblies: Implications for Alzheimer's Disease Downloaded from http://perspectivesinmedicine.cshlp.org/ on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press The Prion-Like Properties of Amyloid-b Assemblies: Implications for Alzheimer’s Disease Lary C. Walker,1 Juliane Schelle,2,3 and Mathias Jucker2,3 1Yerkes National Primate Research Center and Department of Neurology, Emory University, Atlanta, Georgia 30322 2Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tu¨bingen, D-72076 Tu¨bingen, Germany 3German Center for Neurodegenerative Diseases (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 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-b (Ab). 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 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 tau protein (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- proteins 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 Editor: Stanley B. Prusiner Additional Perspectives on Prion Diseases available at www.perspectivesinmedicine.org Copyright # 2016 Cold Spring Harbor Laboratory Press; all rights reserved Advanced Online Article. Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a024398 1 Downloaded from http://perspectivesinmedicine.cshlp.org/ on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press L.C. Walker et al. Figure 1. The canonical histopathology of Alzheimer’s disease (AD). Amyloid-b (Ab) plaques consist of extracellular deposits of Ab (brown; detected by immunostaining 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 neocortex 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 Congo red, a generic stain for amyloid. Scale bar, 200 mm. 2 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a024398 Downloaded from http://perspectivesinmedicine.cshlp.org/ on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press 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 tauopathy 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-amyloidosis 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 proteopathy. 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 amino acid 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 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Med doi:
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