SATURDAY, NOVEMBER 19, 2022
Aβ and tau prions feature in the neuropathogenesis of Down syndrome
Aβ and tau prions feature in the neuropathogenesis of Down syndrome
Carlo Condello carlo.condello@ucsf.edu, Alison M. Maxwell, Erika Castillo https://orcid.org/0000-0003-2492-901X, +9, and Stanley B. Prusiner
stanley.prusiner@ucsf.eduAuthors Info & Affiliations
Contributed by Stanley Prusiner; received August 1, 2022; accepted September 27, 2022; reviewed by Robert Brown Jr. and Neil Cashman.
November 7, 2022
119 (46) e2212954119
Significance
Approximately 5.4 million people worldwide have Down syndrome (DS), which is caused by trisomy of chromosome 21 (Chr21). The APP gene is one of approximately 250 protein-coding genes located on Chr21, and its duplication is associated with elevated Aβ production and increased incidence of Alzheimer’s disease (AD) neuropathology in most aged individuals with DS. Since AD brains have plaques composed of Aβ prions and neurofibrillary tangles composed of tau prions, we asked if DS brains have both Aβ and tau prions. We found that the age-dependent kinetics of Aβ and tau prions are distinct in DS and could even be detected in a 19-y-old individual. Whether DS is an ideal model for assessing efficacy of putative AD therapeutics remains unknown.
Abstract
Down syndrome (DS) is caused by the triplication of chromosome 21 and is the most common chromosomal disorder in humans. Those individuals with DS who live beyond age 40 y develop a progressive dementia that is similar to Alzheimer’s disease (AD). Both DS and AD brains exhibit numerous extracellular amyloid plaques composed of Aβ and intracellular neurofibrillary tangles composed of tau. Since AD is a double-prion disorder, we asked if both Aβ and tau prions feature in DS. Frozen brains from people with DS, familial AD (fAD), sporadic AD (sAD), and age-matched controls were procured from brain biorepositories. We selectively precipitated Aβ and tau prions from DS brain homogenates and measured the number of prions using cellular bioassays. In brain extracts from 28 deceased donors with DS, ranging in age from 19 to 65 y, we found nearly all DS brains had readily measurable levels of Aβ and tau prions. In a cross-sectional analysis of DS donor age at death, we found that the levels of Aβ and tau prions increased with age. In contrast to DS brains, the levels of Aβ and tau prions in the brains of 37 fAD and sAD donors decreased as a function of age at death. Whether DS is an ideal model for assessing the efficacy of putative AD therapeutics remains to be determined.
snip...
Discussion
Our findings demonstrate that the brains of people with DS feature both Aβ and tau prions, which appear to be indistinguishable from the two prions that accumulate in both the sporadic and familial forms of AD. Importantly, DS is neither sporadic nor inherited, but it is a genetic disease caused by complete or partial triplication of Chr21. In trisomic individuals who bear an extra copy of the APP gene, the overexpression of wild-type (WT) APP results in increased levels of Aβ prions. Conversely, partial trisomy lacking triplication of APP does not lead to the neuropathologic changes of AD (50, 51). While we have previously reported that Aβ prions in the absence of tau prions result in cerebral amyloid angiopathy (26), this is not the case for DS. We found both Aβ and tau prions in nearly all of the brains of our DS cohort. In agreement with others, we propose that research in people with DS may help clarify sAD pathogenesis, given that both neuropathology and prion infectivity closely resemble that found in sAD, the predominant form of AD.
Notably, some individuals with DS exhibit many co-occurring conditions, including heart defects, obesity, diabetes, and progeria. How these conditions in people with DS modify the central nervous system dysfunction in the aging DS brain is unclear. There is evidence from mouse models that triplication of some Chr21 homologs increases Aβ deposition independently of an extra APP copy (52); conversely, APP duplication alone is sufficient to cause AD (53). APP duplications in DS provide an interesting comparison to Tg(APP) mice, which also overexpress human APP and Aβ. However, we note that plaques only form in Tg mice bearing familial mutations in APP and not WT APP; efforts to knock-in the WT human APP allele or humanize the Aβ peptide sequence within rodent App do not lead to plaque formation in the lifespan of a mouse (54, 55). Moreover, while the first generation of DS mouse models, segmental trisomy of mouse Chr16 (e.g., Ts65Dn) (56, 57), do replicate many neurodevelopmental phenotypes and present age-related neurodegeneration, they do not produce robust Aβ pathology in aged mice (58). One caveat of the Ts65Dn model is that it duplicates genes not present on human Chr21. To avoid this, new models employing transchromosomic (Tc) techniques in mice and rats have been developed in which the long arm of human Chr21 is cloned into the rodent genome. Despite this advancement, there is still a lack of Aβ plaque formation during the Tc(Chr21) rodent lifespan (59, 60). Whether or not Aβ prions could be measured in Tc(Chr21) rodents using cellular bioassays remains to be determined. Nevertheless, these findings suggest that the formation of Aβ and tau prions as well as AD neuropathology resulting from overexpression of WT human APP is a uniquely human condition. These findings make it critical to use human brain samples wherever possible to investigate the molecular pathogenesis of DS.
Effects of Aβ concentration on the formation of Aβ prion strains may be amenable to study in both rodents and humans. In prior work, we demonstrated that the brain concentrations of APP, Aβ40, and Aβ42 proteins in long-lived people with AD trended significantly lower (P < 0.005) compared with people who died much younger (26). This matches the lower Aβ prion infectivity observed with cell bioassays in those same people (26). If such a trend was present from a young age, it might indicate that low APP expression over the lifespan contributes to an Aβ prion strain that is less pathogenic or slower to accumulate and contributes to longevity. Interestingly, using amyloid strain-sensitive dyes and spectral imaging methods in fixed tissues (61), we found that the conformation of Aβ plaques in aged individuals with DS and advanced neuropathology showed a distinct conformational strain phenotype, compared with sAD (62). While the relationship between amyloid plaque conformation and Aβ prion infectivity remains to be determined, there is growing evidence that supports the notion that pathogenic Aβ and tau species in DS may differ from fAD and sAD in ways not appreciated with traditional histological and biochemical measurements.
Our prion bioassays allow for measurement of both Aβ and tau prions in DS rather than inert protein deposits. The finding that Aβ and tau prions are positively correlated in DS and AD agrees well with genetic and experimental studies arguing that Aβ prions arise early in AD pathogenesis and that these prions initiate subsequent tau prion formation (63–65). Consistent with this notion, we found that samples from two of the youngest individuals with DS in our study (19 and 25 y old) exhibited robust levels of Aβ prions but insignificant levels of tau prions; in adjacent formalin-fixed sections, we found that these donors had low levels of plaques and tangles (SI Appendix, Fig. S2). In contrast, we have not found any brains with DS or AD that have readily detectable levels of tau prions accompanied by marginal levels of Aβ prions. Indeed, our studies of primary tauopathies such as progressive supranuclear palsy and corticobasal degeneration have failed to show any detectable Aβ prions (26). To our knowledge, individuals with DS do not present with only NFTs in the absence of amyloid plaques (15). This finding is consistent with our view that Aβ prions initiate formation of tau NFTs in the vast majority of people with AD as well as DS.
Indeed, the cellular bioassays provide a functional readout of self-replicative proteins but do not provide the biophysical or structural characteristics of a given prion. It will be important for future mechanistic and drug discovery research to more precisely understand the molecular features of Aβ and tau prions in DS and AD. For example, Aβ peptides assemble into aggregates, which are called oligomers when the aggregate size is less than ∼50 peptides (66). A multitude of studies on human brain samples have reported the existence of soluble Aβ oligomers ranging in size, including dimers, trimers, and tetramers (67). Oligomer size has also been found to correlate inversely with cellular toxicity (68, 69). Moreover, the abundance of Aβ oligomers correlates well with the progression of cognitive deficits (70–72) and can differentiate patients with AD from nondemented people with comparable amyloid plaque burden (73). Extensive studies of Aβ oligomers in DS are lacking, but a few reports indicate an early (preplaque accumulation) and persistent increase of Aβ oligomers in aging DS people (74, 75). This is consistent with our data showing abundant Aβ prions in young people with DS with little to no amyloid plaque pathology. To our knowledge, there are no reports describing the characterization of tau oligomers in the brains of DS donors. Whether Aβ or tau multimer size correlates with prion infectivity and pathological deposition remains to be determined. By quantifying the oligomeric distribution and concentration, it should be possible to establish a relationship between the number of proteins in an oligomer and its prion infectivity (i.e., the particle to infectivity ratio [P/I]). For example, the P/I is ∼5,000 for the scrapie PrP isoform (76).
DS reveals a new vista of prion biology where trisomy of Chr21 results in increased Aβ production from an early age and leads to the formation of Aβ prions (77–80). It will be important to determine if this phenomenon occurs in all people with DS or a subset and to establish the earliest ages of prion detection. Despite the extraordinary contrast in etiologies between two genetic forms of Aβ prion diseases, one of which is nonheritable (DS) and the other heritable (fAD), both DS and fAD lead to a convergent neuropathogenic phenotype. Notably, by including sAD with fAD and DS, these three double-prion diseases are the most frequent neurodegenerative conditions worldwide, in which Aβ prions stimulate tau prions to cause neurodegeneration. Moreover, DS joins the expanding spectrum of NDs known to be caused by pathogenic prions (Table 1). Indeed, PrP prions cause Creutzfeldt-Jakob disease and kuru and can manifest in sporadic, heritable, and communicable disorders. While the other NDs can be sporadic or heritable, there is little evidence that Aβ, tau, or α-synuclein prions are communicable or spread by iatrogenic transmission (102–105). However, Aβ, tau, or α-synuclein prions extracted from donor brains of each disease can be transmitted to experimental animals or cultured human cells. These transmission models have enabled investigations of prion disease mechanisms and preclinical testing of novel therapeutic candidates.
Ridley et al. (34) provided the first clues of Aβ prions in the brains of people with DS, but the incubation times in marmosets are much too long for experimental investigations. In contrast, using our rapid cell bioassays, we discovered that the brains of people with DS contain both Aβ and tau prions indistinguishable from those found in AD. Our findings offer an approach to comparative clinical studies of AD and DS. As we learn more about Aβ and tau prions in DS, it may be feasible to develop smaller, shorter, and more informative clinical trials of potential AD treatments (106, 107). Whether advances in human positron emission tomography imaging for both Aβ plaques and NFTs will prove useful in assessing the levels of Aβ and tau prions in the brains of adults with DS who receive putative anti–AD prion therapeutics remains to be established. Last, because the brains of long-lived people with DS exhibit increased prion infectivity, we posit that more molecular studies for people with DS are needed to better understand how age-dependent pathogenic mechanisms in DS cause a divergent prion phenotype from sAD. The outcome of such work may have important implications for developing drugs that are more aptly tailored to improve quality of life for people with DS.
snip...see full text;
Prion 2022 Conference abstracts: pushing the boundaries
terry
No comments:
Post a Comment