RESUMEN
Synucleinopathies are a group of neurodegenerative disorders characterized by the presence of misfolded α-Synuclein (αSyn) in the brain. These conditions manifest with diverse clinical and pathophysiological characteristics. This disease diversity is hypothesized to be driven by αSyn strains with differing biophysical properties, potentially influencing prion-type propagation and consequentially the progression of illness. Previously, we investigated this hypothesis by injecting brain lysate (seeds) from deceased individuals with various synucleinopathies or human recombinant αSyn preformed fibrils (PFFs) into transgenic mice overexpressing either wild type or A53T human αSyn. In the studies herein, we expanded on these experiments, utilizing a panel of antibodies specific for the major carboxyl-terminally truncated forms of αSyn (αSynΔC). These modified forms of αSyn are found enriched in human disease brains to inform on potential strain-specific proteolytic patterns. With monoclonal antibodies specific for human αSyn cleaved at residues 103, 114, 122, 125, and 129, we demonstrate that multiple system atrophy (MSA) seeds and PFFs induce differing neuroanatomical spread of αSyn pathology associated with host specific profiles. Overall, αSyn cleaved at residue 103 was most widely present in the induced pathological inclusions. Furthermore, αSynΔC-positive inclusions were present in astrocytes, but more frequently in activated microglia, with patterns dependent on host and inoculum. These findings support the hypothesis that synucleinopathy heterogeneity might stem from αSyn strains with unique biochemical properties that include proteolytic processing, which could result in dominant strain properties.
Asunto(s)
Encéfalo , Modelos Animales de Enfermedad , Ratones Transgénicos , alfa-Sinucleína , alfa-Sinucleína/metabolismo , alfa-Sinucleína/inmunología , Animales , Humanos , Ratones , Encéfalo/patología , Encéfalo/metabolismo , Sinucleinopatías/patología , Sinucleinopatías/metabolismo , Sinucleinopatías/inmunología , Anticuerpos Monoclonales , Atrofia de Múltiples Sistemas/patología , Atrofia de Múltiples Sistemas/inmunología , Atrofia de Múltiples Sistemas/metabolismo , Priones/inmunología , Priones/metabolismo , FemeninoRESUMEN
Enhancing production of protein cargoes delivered by gene therapies can improve efficacy by reducing the amount of vector or simply increasing transgene expression levels. We explored the utility of a 126-amino acid collagen domain (CD) derived from the C1qTNF3 protein as a fusion partner to chaperone secreted proteins, extracellular "decoy receptor" domains, and single-chain variable fragments (scFvs). Fusions to the CD domain result in multimerization and enhanced levels of secretion of numerous fusion proteins while maintaining functionality. Efficient creation of bifunctional proteins using the CD domain is also demonstrated. Recombinant adeno-associated viral vector delivery of the CD with a signal peptide resulted in high-level expression with minimal biological impact as assessed by whole-brain transcriptomics. As a proof-of-concept in vivo study, we evaluated three different anti-amyloid Aß scFvs (anti-Aß scFvs), alone or expressed as CD fusions, following viral delivery to neonatal CRND8 mice. The CD fusion increased half-life, expression levels, and improved efficacy for amyloid lowering of a weaker binding anti-Aß scFv. These studies validate the potential utility of this small CD as a fusion partner for secretory cargoes delivered by gene therapy and demonstrate that it is feasible to use this CD fusion to create biotherapeutic molecules with enhanced avidity or bifunctionality.
RESUMEN
Distinctive post-translational modifications (PTM) characterize tau inclusions found in tauopathy patients. Using detergent-insoluble tau isolated from Alzheimer's disease (AD-tau) or Progressive Supranuclear Palsy (PSP-tau) patients, we provide insights into whether phosphorylation of critical residues determine templated tau seeding. Our initial data with phosphorylation-ablating mutations (Ser/Thr â Ala) on select sites of P301L tau showed no changes in seeding efficacy by AD-tau or PSP-tau. Interestingly, when specific sites in the R1-R2 repeat domains (Ser262/Thr263/Ser289/Ser305) were mutated to phosphorylation-mimicking amino acid Glu, it substantially reduced the seeding efficiency of AD-tau, but not PSP-tau seeds. The resultant detergent-insoluble tau shows deficient phosphorylation on AT8, AT100, AT180 and PHF1 epitopes, indicating inter-domain cooperativity. We further identify Ser305 as a critical determinant of AD-tau-specific seeding, whereby the phospho-mimicking Ser305Glu tau abrogates seeding by AD-tau but not PSP-tau. This suggests that phosphorylation on Ser305 could be related to the formation of disease-specific tau strains. Our results highlight the existence of a phospho-PTM code in tau seeding and further demonstrate the distinctive nature of this code in 4R tauopathies.
Asunto(s)
Enfermedad de Alzheimer , Tauopatías , Humanos , Proteínas tau/metabolismo , Fosforilación , Detergentes , Tauopatías/genética , Tauopatías/metabolismo , Enfermedad de Alzheimer/metabolismoRESUMEN
Tau proteins within the adult central nervous system (CNS) are found to be abnormally aggregated into heterogeneous filaments in neurodegenerative diseases, termed tauopathies. These tau inclusions are pathological hallmarks of Alzheimer's disease (AD), Pick's disease (PiD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP). The neuropathological hallmarks of these diseases burden several cell types within the CNS, and have also been shown to be abundantly phosphorylated. The mechanism(s) by which tau aggregates in the CNS is not fully known, but it is hypothesized that hyperphosphorylated tau may precede and further promote filament formation, leading to the production of these pathological inclusions. In the studies herein, we generated and thoroughly characterized two novel conformation-dependent tau monoclonal antibodies that bind to residues Pro218-Glu222, but are sensitive to denaturing conditions and highly modulated by adjacent downstream phosphorylation sites. These epitopes are present in the neuropathological hallmarks of several tauopathies, including AD, PiD, CBD, and PSP. These novel antibodies will further enable investigation of tau-dependent pathological inclusion formation and enhance our understanding of the phosphorylation signatures within tauopathies with the possibility of new biomarker developments.
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Enfermedad de Alzheimer , Enfermedad de Pick , Tauopatías , Adulto , Humanos , Fosforilación , Anticuerpos Monoclonales , Sistema Nervioso CentralRESUMEN
Post-translational modifications to the carboxyl (C) terminus domain of α-synuclein can play an important role in promoting the pathologic aggregation of α-synuclein. Various cleavages that diminish this highly charged, proline-rich region can result in exposure of hydrophobic, aggregation-prone regions, thereby accelerating the aggregation kinetics of α-synuclein into misfolded, pathologic forms. C-terminally truncated forms of α-synuclein are abundant in human diseased brains compared to controls, suggesting a role in disease pathogenesis. Factors that alter the homeostatic proteolytic processing of α-synuclein may ultimately tip the balance towards a progressive disease state. Apolipoprotein E (APOE) has been implicated in the acceleration of cognitive impairment in patients with Lewy body diseases. The APOE4 isoform has been found to cause dysregulation in the endosomal-lysosomal pathway, which could result in altered α-synuclein degradation as a potential mechanism for promoting its pathologic misfolding. Herein, we investigate the spatiotemporal accumulation of C-terminally truncated α-synuclein in a seeded and progressive mouse model of synucleinopathy. Furthermore, we study how this process is influenced in the context of mice that are altered to express either the human APOE3 or APOE4 isoforms. We found that specific C-terminal truncation of α-synuclein occurs at early stages of pathogenesis. We also found that proteolytic processing of this domain differs across various brain regions and is influenced by the presence of different human APOE isoforms. Our data demonstrate an early pathogenic role for C-terminally truncated α-synuclein, and highlight the influence of APOE isoforms in modulating its impact.
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Apolipoproteína E4 , alfa-Sinucleína , Animales , Humanos , Ratones , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Apolipoproteínas E/metabolismo , Proteínas Portadoras , Ratones Transgénicos , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismoRESUMEN
Tauopathies are a group of neurodegenerative diseases, which include frontotemporal dementia (FTD) and Alzheimer's disease (AD), broadly defined by the development of tau brain aggregates. Both missense and splicing tau mutations can directly cause early onset FTD. Tau protein is a microtubule-associated protein that stabilizes and regulates microtubules, but this function can be disrupted in disease states. One contributing factor is the balance of different tau isoforms, which can be categorized into either three repeat (3R) or four repeat (4R) isoforms based on the number of microtubule-binding repeats that are expressed. Imbalance of 3R and 4R isoforms in either direction can cause FTD and neurodegeneration. There is also increasing evidence that 3R tauopathies such as Pick's disease form tau aggregates predominantly comprised of 3R isoforms and these can present differently from 4R and mixed 3R/4R tauopathies. In this study, multiple mutations in 3R tau were assessed for MT binding properties and prion-like aggregation propensity. Different missense tau mutations showed varying effects on MT binding depending on molecular location and properties. Of the mutations that were surveyed, S356T tau is uniquely capable of prion-like seeded aggregation and forms extensive Thioflavin positive aggregates. This unique prion-like tau strain will be useful to model 3R tau aggregation and will contribute to the understanding of diverse presentations of different tauopathies.
RESUMEN
α-synuclein (αS) is an abundant, neuronal protein that assembles into fibrillar pathological inclusions in a spectrum of neurodegenerative diseases that include Lewy body diseases (LBD) and Multiple System Atrophy (MSA). The cellular and regional distributions of pathological inclusions vary widely between different synucleinopathies contributing to the spectrum of clinical presentations. Extensive cleavage within the carboxy (C)-terminal region of αS is associated with inclusion formation, although the events leading to these modifications and the implications for pathobiology are of ongoing study. αS preformed fibrils can induce prion-like spread of αS pathology in both in vitro and animal models of disease. Using C truncation-specific antibodies, we demonstrated here that prion-like cellular uptake and processing of αS preformed fibrils resulted in two major cleavages at residues 103 and 114. A third cleavage product (122 αS) accumulated upon application of lysosomal protease inhibitors. In vitro, both 1-103 and 1-114 αS polymerized rapidly and extensively in isolation and in the presence of full-length αS. 1-103 αS also demonstrated more extensive aggregation when expressed in cultured cells. Furthermore, we used novel antibodies to αS cleaved at residue Glu114, to assess x-114 αS pathology in postmortem brain tissue from patients with LBD and MSA, as well as three different transgenic αS mouse models of prion-like induction. The distribution of x-114 αS pathology was distinct from that of overall αS pathology. These studies reveal the cellular formation and behavior of αS C-truncated at residues 114 and 103 as well as the disease dependent distribution of x-114 αS pathology.
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Enfermedad por Cuerpos de Lewy , Atrofia de Múltiples Sistemas , alfa-Sinucleína , Animales , Ratones , alfa-Sinucleína/química , alfa-Sinucleína/metabolismo , Ratones Transgénicos , Atrofia de Múltiples Sistemas/metabolismo , Atrofia de Múltiples Sistemas/patología , Priones/química , Priones/metabolismo , Humanos , Lisosomas/enzimología , Inhibidores de Proteasas , Enfermedad por Cuerpos de Lewy/metabolismo , Enfermedad por Cuerpos de Lewy/patología , Autopsia , Ácido Glutámico/metabolismoRESUMEN
Alzheimer's disease (AD) and frontotemporal dementia (FTD) can be classified as tauopathies, which are a group of neurodegenerative diseases that develop toxic tau aggregates in specific brain regions. These pathological tau inclusions are altered by various post-translational modifications (PTMs) that include phosphorylation, acetylation, and methylation. Tau methylation has emerged as a target of interest for its potential involvement in tau pathomechanisms. Filamentous tau aggregates isolated from patients with AD are methylated at multiple lysine residues, although the exact methyltransferases have not been identified. One strategy to study the site-specific effects of methylation is to create methylation mimetics using a KFC model, which replaces lysine (K) with a hydrophobic group such as phenylalanine (F) to approximate the effects of lysine methylation (C or methyl group). In this study, tau methylmimetics were used to model several functional aspects of tau methylation such as effects on microtubule binding and tau aggregation in cell models. Overall, several tau methylmimetics displayed impaired microtubule binding, and tau methylmimetics enhanced prion-like seeded aggregation in the context of the FTD tau mutation P301L. Like other PTMs, tau methylation is a contributing factor to tau pathogenesis and could be a potential therapeutic drug target for the treatment of different tauopathies.
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Enfermedad de Alzheimer , Demencia Frontotemporal , Enfermedad de Pick , Priones , Tauopatías , Humanos , Proteínas tau/metabolismo , Lisina/metabolismo , Priones/metabolismo , Demencia Frontotemporal/genética , Demencia Frontotemporal/metabolismo , Enfermedad de Alzheimer/metabolismo , Tauopatías/metabolismo , Enfermedad de Pick/metabolismo , Microtúbulos/metabolismoRESUMEN
Aggregated α-synuclein, a major constituent of Lewy bodies plays a crucial role in the pathogenesis of α-synucleinopathies (SPs) such as Parkinson's disease (PD). PD is affected by the innate and adaptive arms of the immune system, and recently both active and passive immunotherapies targeted against α-synuclein are being trialed as potential novel treatment strategies. Specifically, dendritic cell-based vaccines have shown to be an effective treatment for SPs in animal models. Here, we report on the development of adoptive cellular therapy (ACT) for SP and demonstrate that adoptive transfer of pre-activated T-cells generated from immunized mice can improve survival and behavior, reduce brain microstructural impairment via magnetic resonance imaging (MRI), and decrease α-synuclein pathology burden in a peripherally induced preclinical SP model (M83) when administered prior to disease onset. This study provides preclinical evidence for ACT as a potential immunotherapy for LBD, PD and other related SPs, and future work will provide necessary understanding of the mechanisms of its action.
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Enfermedad de Parkinson , Sinucleinopatías , Vacunas , Ratones , Animales , alfa-Sinucleína/genética , Sinucleinopatías/patología , Ratones Transgénicos , Enfermedad de Parkinson/terapia , Enfermedad de Parkinson/patología , Modelos Animales de EnfermedadRESUMEN
The relative polymerization of specific tau protein cores that define Alzheimer's disease, Pick's disease and corticobasal degeneration were investigated using amyloid fluorometry and electron microscopy. In addition, the relative prion-like activities of polymers comprised of these respective tau protein segments were investigated in a cell-based assay. It is demonstrated that the seeding activities of specific tau core fibrils are affected by the presence of pathogenic tau missense mutations and the microtubule binding domain composition of tau. The unique impact of tau phosphorylation on seeding propensity was also investigated by altering stretches of phospho-mimetic and phospho-null residues in the presence of Alzheimer's disease tau core fibrils. These results have important mechanistic implications for mutation and isoform-specific driven pathogenesis.
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The accumulation of α-synuclein (α-syn) in intracellular formations known as Lewy bodies (LBs) is associated with several neurodegenerative diseases including Parkinson's disease and Lewy Body Dementia. There is still limited understanding of how α-syn and LB formation is associated with cellular dysfunction and degeneration in these diseases. To examine the clearance and production dynamics of α-syn we transduced organotypic murine brain slice cultures (BSCs) with recombinant adeno-associated viruses (rAAVs) to express Dendra2-tagged human wild-type (WT) and mutant A53T α-syn, with and without the addition of exogenous α-syn fibrillar seeds and tracked them over several weeks in culture using optical pulse labeling. We found that neurons expressing WT or mutant A53T human α-syn show similar rates of α-syn turnover even when insoluble, phosphorylated Ser129 α-syn has accumulated. Taken together, this data reveals α-syn aggregation and overexpression, pSer129 α-syn, nor the A53T mutation affect α-syn dynamics in this system. Prion-type seeding with exogenous α-syn fibrils significantly slows α-syn turnover, in the absence of toxicity but is associated with the accumulation of anti-p62 immunoreactivity and Thiazin Red positivity. Prion-type induction of α-syn aggregation points towards a potential protein clearance deficit in the presence of fibrillar seeds and the ease of this system to explore precise mechanisms underlying these processes. This system facilitates the exploration of α-syn protein dynamics over long-term culture periods. This platform can further be exploited to provide mechanistic insight on what drives this slowing of α-syn turnover and how therapeutics, other genes or different α-syn mutations may affect α-syn protein dynamics.
RESUMEN
MHCII molecules, expressed by professional antigen-presenting cells (APCs) such as T cells and B cells, are hypothesized to play a key role in the response of cellular immunity to α-synuclein (α-syn). However, the role of cellular immunity in the neuroanatomic transmission of α-syn pre-formed fibrillar (PFF) seeds is undetermined. To illuminate whether cellular immunity influences the transmission of α-syn seeds from the periphery into the CNS, we injected preformed α-syn PFFs in the hindlimb of the Line M83 transgenic mouse model of synucleinopathy lacking MhcII. We showed that a complete deficiency in MhcII accelerated the appearance of seeded α-syn pathology and shortened the lifespan of the PFF-seeded M83 mice. To characterize whether B-cell and T-cell inherent MhcII function underlies this accelerated response to PFF seeding, we next injected α-syn PFFs in Rag1-/- mice which completely lacked these mature lymphocytes. There was no alteration in the lifespan or burden of endstage α-syn pathology in the PFF-seeded, Rag1-deficient M83+/- mice. Together, these results suggested that MhcII function on immune cells other than these classical APCs is potentially involved in the propagation of α-syn in this model of experimental synucleinopathy. We focused on microglia next, finding that while microglial burden was significantly upregulated in PFF-seeded, MhcII-deficient mice relative to controls, the microglial activation marker Cd68 was reduced in these mice, suggesting that these microglia were not responsive. Additional analysis of the CNS showed the early appearance of the neurotoxic astrocyte A1 signature and the induction of the Ifnγ-inducible anti-viral response mediated by MhcI in the MhcII-deficient, PFF-seeded mice. Overall, our data suggest that the loss of MhcII function leads to a dysfunctional response in non-classical APCs and that this response could potentially play a role in determining PFF-induced pathology. Collectively, our results identify the critical role of MhcII function in synucleinopathies induced by α-syn prion seeds.
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Sinucleinopatías , Animales , Proteínas de Homeodominio , Ratones , Ratones Transgénicos , Microglía , alfa-Sinucleína/genéticaRESUMEN
Tau is a predominantly neuronal, soluble and natively unfolded protein that can bind and stabilize microtubules in the central nervous system. Tau has been extensively studied over several decades, especially in the context of neurodegenerative diseases where it can aberrantly aggregate to form a spectrum of pathological inclusions. The presence of tau inclusions in the form of neurofibrillary tangles, neuropil threads and dystrophic neurites within senile plaques are essential and defining features of Alzheimer's disease. The current dogma favors the notion that tau is predominantly an axonal protein, and that in Alzheimer's disease there is a redistribution of tau towards the neuronal soma that is associated with the formation of pathological inclusions such as neurofibrillary tangles and neuropil threads. Using novel as well as previously established highly specific tau antibodies, we demonstrate that contrary to this overwhelmingly accepted fact, as asserted in numerous articles and reviews, in adult human brain, tau is more abundant in cortical gray matter that is enriched in neuronal soma and dendrites compared to white matter that is predominantly rich in neuronal axons. Additionally, in Alzheimer's disease tau pathology is significantly more abundant in the brain cortical gray matter of affected brain regions compared to the adjacent white matter regions. These findings have important implications for the biological function of tau as well as the mechanisms involved in the progressive spread of tau associated with the insidious nature of Alzheimer's disease.
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Enfermedad de Alzheimer , Adulto , Enfermedad de Alzheimer/patología , Encéfalo/patología , Humanos , Ovillos Neurofibrilares/patología , Neuronas/metabolismo , Proteínas tau/metabolismoRESUMEN
Pathological tau inclusions are neuropathologic hallmarks of many neurodegenerative diseases. We generated and characterized a transgenic mouse model expressing pathogenic human tau with S320F and P301S aggregating mutations (SPAM) at transgene levels below endogenous mouse tau protein levels. This mouse model develops a predictable temporal progression of tau pathology in the brain with biochemical and ultrastructural properties akin to authentic tau inclusions. Surprisingly, pathogenic human tau extensively recruited endogenous mouse tau into insoluble aggregates. Despite the early onset and rapid progressive nature of tau pathology, major neuroinflammatory and transcriptional changes were only detectable at later time points. Moreover, tau SPAM mice are the first model to develop loss of enteric neurons due to tau accumulation resulting in a lethal phenotype. With moderate transgene expression, rapidly progressing tau pathology, and a highly predictable lethal phenotype, the tau SPAM model reveals new associations of tau neurotoxicity in the brain and intestinal tract.
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Encéfalo , Proteínas tau , Animales , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Transgénicos , Mutación , Neuronas/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismoRESUMEN
Background: Seeding of pathology related to Alzheimer's disease (AD) and Lewy body disease (LBD) by tissue homogenates or purified protein aggregates in various model systems has revealed prion-like properties of these disorders. Typically, these homogenates are injected into adult mice stereotaxically. Injection of brain lysates into newborn mice represents an alternative approach of delivering seeds that could direct the evolution of amyloid-ß (Aß) pathology co-mixed with either tau or α-synuclein (αSyn) pathology in susceptible mouse models. Methods: Homogenates of human pre-frontal cortex were injected into the lateral ventricles of newborn (P0) mice expressing a mutant humanized amyloid precursor protein (APP), human P301L tau, human wild type αSyn, or combinations thereof. The homogenates were prepared from AD and AD/LBD cases displaying variable degrees of Aß pathology and co-existing tau and αSyn deposits. Behavioral assessments of APP transgenic mice injected with AD brain lysates were conducted. For comparison, homogenates of aged APP transgenic mice that preferentially exhibit diffuse or cored deposits were similarly injected into the brains of newborn APP mice. Results: We observed that lysates from the brains with AD (Aß+, tau+), AD/LBD (Aß+, tau+, αSyn+), or Pathological Aging (Aß+, tau-, αSyn-) efficiently seeded diffuse Aß deposits. Moderate seeding of cerebral amyloid angiopathy (CAA) was also observed. No animal of any genotype developed discernable tau or αSyn pathology. Performance in fear-conditioning cognitive tasks was not significantly altered in APP transgenic animals injected with AD brain lysates compared to nontransgenic controls. Homogenates prepared from aged APP transgenic mice with diffuse Aß deposits induced similar deposits in APP host mice; whereas homogenates from APP mice with cored deposits induced similar cored deposits, albeit at a lower level. Conclusions: These findings are consistent with the idea that diffuse Aß pathology, which is a common feature of human AD, AD/LBD, and PA brains, may arise from a distinct strain of misfolded Aß that is highly transmissible to newborn transgenic APP mice. Seeding of tau or αSyn comorbidities was inefficient in the models we used, indicating that additional methodological refinement will be needed to efficiently seed AD or AD/LBD mixed pathologies by injecting newborn mice.
RESUMEN
Apolipoprotein (APOE) is a major risk factor of Alzheimer's disease (AD), with the E2, E3 and E4 isoforms differentially regulating the burden of AD-associated neuropathologies, such as amyloid ß and tau. In AD, pathological tau is thought to spread along neuroanatomic connections following a prion-like mechanism. To provide insights into whether APOE isoforms differentially regulate the prion properties of tau and determine trans-synaptic transmission of tauopathy, we have generated human P301S mutant tau transgenic mice (PS19) that carry human APOE (APOE2, APOE3 or APOE4) or mouse Apoe allele. Mice received intrahippocamal injections of preformed aggregates of K18-tau at young ages, which were analyzed 5 months post-inoculation. Compared to the parental PS19 mice with mouse Apoe alleles, PS19 mice expressing human APOE alleles generally responded to K18-tau seeding with more intense AT8 immunoreactive phosphorylated tau athology. APOE3 homozygous mice accumulated higher levels of AT8-reactive ptau and microgliosis relative to APOE2 or APOE4 homozygotes (E3 > E4~2). PS19 mice that were heterozygous for APOE3 showed similar results, albeit to a lesser degree. In the timeframe of our investigation, we did not observe significant induction of argentophilic or MC1-reactive neurofibrillary tau tangle in PS19 mice homozygous for human APOE. To our knowledge, this is the first comprehensive study in rodent models that provides neuropathological insights into the dose-dependent effect of APOE isoforms on phosphorylated tau pathology induced by recombinant tau prions.
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Enfermedad de Alzheimer , Apolipoproteínas E/metabolismo , Priones , Tauopatías , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/genética , Animales , Apolipoproteína E2/genética , Apolipoproteína E3/genética , Apolipoproteína E4/genética , Apolipoproteínas E/genética , Genotipo , Humanos , Ratones , Ratones Transgénicos , Priones/genética , Isoformas de Proteínas/genética , Tauopatías/complicaciones , Tauopatías/genéticaRESUMEN
[This corrects the article DOI: 10.1093/braincomms/fcab104.].