RESUMO
BACKGROUND: Cholinesterase inhibitors (ChEIs) are prescribed for Alzheimer's disease (AD) and sometimes for mild cognitive impairment (MCI) without knowing underlying pathologies and its effect on cognition. We investigated the frequency of ChEI prescriptions in amyloid-negative MCI and their association with cognitive changes in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. METHODS: We included participants with amyloid positron emission tomography (PET)-negative MCI from the ADNI. We analyzed the associations of ChEI use with cognitive changes, brain volume, and cerebrospinal fluid (CSF) total tau (t-tau), hyperphosphorylated tau181 (p-tau181), and p-tau181/t-tau ratio. RESULTS: ChEIs were prescribed in 27.4% of amyloid PET-negative MCI and were associated with faster cognitive decline, reduced baseline hippocampal volume and entorhinal cortical thickness, and a longitudinal decrease in the frontal lobe cortical thickness. CONCLUSIONS: The association between ChEI use and accelerated cognitive decline may stem from underlying pathologies involving reduced hippocampal volume, entorhinal cortical thickness and faster frontal lobe atrophy. We suggest that ChEI use in amyloid PET-negative MCI patients might need further consideration, and studies investigating the causality between ChEI use and cognitive decline are warranted in the future.
Assuntos
Inibidores da Colinesterase , Disfunção Cognitiva , Tomografia por Emissão de Pósitrons , Humanos , Disfunção Cognitiva/diagnóstico por imagem , Masculino , Tomografia por Emissão de Pósitrons/métodos , Feminino , Idoso , Inibidores da Colinesterase/uso terapêutico , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/metabolismo , Idoso de 80 Anos ou mais , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Amiloide/metabolismoRESUMO
BACKGROUND: Recent advances in blood-based biomarker discovery are paving the way for simpler, more accessible diagnostic tools that can detect early signs of Alzheimer's disease (AD). Recent successes in the development of amyloid-targeting immunotherapy approaches mark an important advancement in providing new options for the treatment of AD. We have developed a set of high-affinity monoclonal antibodies (mAbs) to tau protein that have the potential as tools for diagnosis and treatment of AD. METHODS: Sheep were immunised with either full-length tau (1-441) or truncated paired helical filament (PHF)-core tau (297-391). A stringent bio-panning and epitope selection strategy, with a particular focus directed to epitopes within the disease-relevant PHF-core tau, was used to identify single-chain antibodies (scAbs). These scAbs were ranked by affinity for each epitope class, with leads converted to high-affinity mAbs. These antibodies and their potential utility were assessed by their performance in tau immunoassays, as well as their ability to prevent tau aggregation and propagation. Further characterisation of these antibodies was performed by immunohistochemical staining of brain sections and immuno-gold electronmicroscopy of isolated PHFs. RESULTS: Our work resulted in a set of high-affinity antibodies reacting with multiple epitopes spanning the entire tau protein molecule. The tau antibodies directed against the core tau unit of the PHF inhibited pathological aggregation and seeding using several biochemical and cell assay systems. Through staining of brain sections and PHFs, the panel of antibodies revealed which tau epitopes were available, truncated, or occluded. In addition, highly sensitive immunoassays were developed with the ability to distinguish between and quantify various tau fragments. CONCLUSION: This article introduces an alternative immunodiagnostic approach based on the concept of a "tauosome" - the diverse set of tau fragments present within biological fluids. The development of an antibody panel that can distinguish a range of different tau fragments provides the basis for a novel approach to potential diagnosis and monitoring of disease progression. Our results further support the notion that tau immunotherapy targeting the PHF-core needs to combine appropriate selection of both the target epitope and antibody affinity to optimise therapeutic potential.
Assuntos
Doença de Alzheimer , Anticorpos Monoclonais , Proteínas tau , Proteínas tau/imunologia , Proteínas tau/metabolismo , Doença de Alzheimer/imunologia , Doença de Alzheimer/terapia , Doença de Alzheimer/diagnóstico , Animais , Ovinos , Anticorpos Monoclonais/imunologia , Humanos , Encéfalo/metabolismo , Encéfalo/imunologia , Encéfalo/patologia , Epitopos/imunologiaRESUMO
Positron Emission Tomography (PET) ligands have advanced Alzheimer's disease (AD) diagnosis and treatment. Using autoradiography and cryo-EM, we identify AD brain tissue with elevated tau burden, purify filaments, and determine the structure of second-generation high avidity PET ligand MK-6240 at 2.31 Å resolution, which bound at a 1:1 ratio within the cleft of tau paired-helical filament (PHF), engaging with glutamine 351, lysine 353, and isoleucine 360. This information elucidates the basis of MK-6240 PET in quantifying PHF deposits in AD and may facilitate the structure-based design of superior ligands against tau amyloids.
Assuntos
Doença de Alzheimer , Microscopia Crioeletrônica , Tomografia por Emissão de Pósitrons , Proteínas tau , Doença de Alzheimer/metabolismo , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Proteínas tau/metabolismo , Proteínas tau/química , Proteínas tau/ultraestrutura , Tomografia por Emissão de Pósitrons/métodos , Humanos , Microscopia Crioeletrônica/métodos , Ligantes , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/patologia , Autorradiografia , Feminino , Masculino , CarbolinasRESUMO
Brain protein aggregates are a hallmark of neurodegenerative disease. Previous work indicates that specific protein components of these aggregates are toxic, including tau (encoded by MAPT) in Alzheimer's disease and related tauopathies. Increasing evidence also indicates that these toxic proteins traffic between cells in a prion-like fashion, thereby spreading pathology from one brain region to another. However, the mechanisms involved in trafficking are poorly understood. We therefore developed a transgenic Drosophila model to facilitate rapid evaluation of candidate tau trafficking modifiers. Our model uses the bipartite Q system to drive co-expression of tau and GFP in the fly eye. We found age-dependent spread of tau into the brain, represented by detection of tau, but not of GFP. We also found that tau trafficking was attenuated upon inhibition of the endocytic factor dynamin (encoded by shi) or knockdown of glycogen synthase kinase-3ß (GSK-3ß, encoded by sgg). Further work revealed that dynamin promoted tau uptake in recipient tissues, whereas GSK-3ß appeared to promote tau spread via direct phosphorylation of tau. Our robust and flexible system will promote the identification of tau-trafficking components involved in the pathogenesis of neurodegenerative diseases.
Assuntos
Animais Geneticamente Modificados , Modelos Animais de Doenças , Proteínas de Drosophila , Drosophila melanogaster , Glicogênio Sintase Quinase 3 beta , Proteínas tau , Animais , Proteínas tau/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Fosforilação , Encéfalo/metabolismo , Encéfalo/patologia , Dinaminas/metabolismo , Transporte Proteico , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Proteínas de Fluorescência Verde/metabolismoRESUMO
Alzheimer's disease is associated with the misfolding and aggregation of two distinct proteins, beta-amyloid and tau. Previously, it has been shown that activation of the cytoprotective heat shock response (HSR) pathway reduces beta-amyloid toxicity. Here, we show that activation of the HSR is also protective against tau toxicity in a cell-autonomous manner. Overexpression of HSF-1, the master regulator of the HSR, ameliorates the motility defect and increases the lifespan of transgenic C. elegans expressing human tau. By contrast, RNA interference of HSF-1 exacerbates the motility defect and shortens lifespan. Targeting regulators of the HSR also affects tau toxicity. Additionally, two small-molecule activators of the HSR, Geranylgeranylacetone (GGA) and Arimoclomol (AC), have substantial beneficial effects. Taken together, this research expands the therapeutic potential of HSR manipulation to tauopathies and reveals that the HSR can impact both beta-amyloid and tau proteotoxicity in Alzheimer's disease.
Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Diterpenos , Resposta ao Choque Térmico , Proteínas tau , Proteínas tau/metabolismo , Resposta ao Choque Térmico/efeitos dos fármacos , Animais , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/efeitos dos fármacos , Humanos , Diterpenos/farmacologia , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Animais Geneticamente Modificados , Longevidade/efeitos dos fármacos , Doença de Alzheimer/patologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/toxicidade , Fatores de TranscriçãoRESUMO
Progressive supranuclear palsy (PSP), a rare Parkinsonian disorder, is characterized by problems with movement, balance, and cognition. PSP differs from Alzheimer's disease (AD) and other diseases, displaying abnormal microtubule-associated protein tau by both neuronal and glial cell pathologies. Genetic contributors may mediate these differences; however, the genetics of PSP remain underexplored. Here we conduct the largest genome-wide association study (GWAS) of PSP which includes 2779 cases (2595 neuropathologically-confirmed) and 5584 controls and identify six independent PSP susceptibility loci with genome-wide significant (P < 5 × 10-8) associations, including five known (MAPT, MOBP, STX6, RUNX2, SLCO1A2) and one novel locus (C4A). Integration with cell type-specific epigenomic annotations reveal an oligodendrocytic signature that might distinguish PSP from AD and Parkinson's disease in subsequent studies. Candidate PSP risk gene prioritization using expression quantitative trait loci (eQTLs) identifies oligodendrocyte-specific effects on gene expression in half of the genome-wide significant loci, and an association with C4A expression in brain tissue, which may be driven by increased C4A copy number. Finally, histological studies demonstrate tau aggregates in oligodendrocytes that colocalize with C4 (complement) deposition. Integrating GWAS with functional studies, epigenomic and eQTL analyses, we identify potential causal roles for variation in MOBP, STX6, RUNX2, SLCO1A2, and C4A in PSP pathogenesis.
Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas , Paralisia Supranuclear Progressiva , Proteínas tau , Humanos , Paralisia Supranuclear Progressiva/genética , Paralisia Supranuclear Progressiva/patologia , Paralisia Supranuclear Progressiva/metabolismo , Idoso , Masculino , Feminino , Proteínas tau/genética , Proteínas tau/metabolismo , Transcriptoma , Polimorfismo de Nucleotídeo Único , Neuroglia/metabolismo , Neuroglia/patologia , Idoso de 80 Anos ou mais , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Pessoa de Meia-Idade , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Doença de Alzheimer/metabolismo , Estudos de Casos e Controles , Proteínas da MielinaRESUMO
Age-related neurodegenerative disorders like Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by deposits of protein aggregates, or amyloid, in various regions of the brain. Historically, aggregation of a single protein was observed to be correlated with these different pathologies: tau in AD and α-synuclein (αS) in PD. However, there is increasing evidence that the pathologies of these two diseases overlap, and the individual proteins may even promote each other's aggregation. Both tau and αS are intrinsically disordered proteins (IDPs), lacking stable secondary and tertiary structure under physiological conditions. In this study we used a combination of biochemical and biophysical techniques to interrogate the interaction of tau with both soluble and fibrillar αS. Fluorescence correlation spectroscopy (FCS) was used to assess the interactions of specific domains of fluorescently labeled tau with full length and C-terminally truncated αS in both monomer and fibrillar forms. We found that full-length tau as well as individual tau domains interact with monomer αS weakly, but this interaction is much more pronounced with αS aggregates. αS aggregates also mildly slow the rate of tau aggregation, although not the final degree of aggregation. Our findings suggest that co-occurrence of tau and αS in disease are more likely to occur through monomer-fiber binding interactions, rather than monomer-monomer or co-aggregation.
Assuntos
alfa-Sinucleína , Proteínas tau , alfa-Sinucleína/metabolismo , alfa-Sinucleína/química , Proteínas tau/metabolismo , Proteínas tau/química , Humanos , Ligação Proteica , Agregados Proteicos , Amiloide/metabolismo , Amiloide/química , Espectrometria de Fluorescência , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Agregação Patológica de Proteínas/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologiaRESUMO
Sleep and circadian rhythm dysfunctions are common clinical features of Alzheimer's disease (AD). Increasing evidence suggests that in addition to being a symptom, sleep disturbances can also drive the progression of neurodegeneration. Protein aggregation is a pathological hallmark of AD; however, the molecular pathways behind how sleep affects protein homeostasis remain elusive. Here we demonstrate that sleep modulation influences proteostasis and the progression of neurodegeneration in Drosophila models of tauopathy. We show that sleep deprivation enhanced Tau aggregational toxicity resulting in exacerbated synaptic degeneration. In contrast, sleep induction using gaboxadol led to reduced toxic Tau accumulation in neurons as a result of modulated autophagic flux and enhanced clearance of ubiquitinated Tau, suggesting altered protein processing and clearance that resulted in improved synaptic integrity and function. These findings highlight the complex relationship between sleep and regulation of protein homeostasis and the neuroprotective potential of sleep-enhancing therapeutics to slow the progression or delay the onset of neurodegeneration.
Assuntos
Doença de Alzheimer , Autofagia , Modelos Animais de Doenças , Proteostase , Sono , Proteínas tau , Animais , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Sono/fisiologia , Proteínas tau/metabolismo , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Neurônios/metabolismo , Drosophila melanogaster/metabolismo , Humanos , Drosophila , Privação do Sono/metabolismo , Privação do Sono/fisiopatologia , Tauopatias/metabolismo , Tauopatias/patologia , Tauopatias/etiologiaRESUMO
Alzheimer's disease (AD) and more than twenty other dementias, termed tauopathies, are pathologically defined by insoluble aggregates of the microtubule-associated protein tau (MAPT). Although tau aggregation correlates with AD symptomology, the specific tau species, i.e., monomers, soluble oligomers, and insoluble aggregates that induce neurotoxicity are incompletely understood. We developed a light-responsive tau protein (optoTAU) and used viscosity-sensitive AggFluor probes to investigate the consequence(s) of tau aggregation in human neurons and identify modifiers of tau aggregation in AD and other tauopathies. We determined that optoTAU reproduces biological and structural properties of tau aggregation observed in human brains and the pathophysiological transition in tau solubility in live cells. We also provide proof-of-concept for the utilization of optoTAU as a pharmacological platform to identify modifiers of tau aggregation. These findings have broad implications for the characterization of aggregation-prone proteins and investigation of the complex relationship between protein solubility, cellular function, and disease progression.
Assuntos
Neurônios , Agregação Patológica de Proteínas , Proteínas tau , Proteínas tau/metabolismo , Proteínas tau/química , Humanos , Neurônios/metabolismo , Agregação Patológica de Proteínas/metabolismo , Agregados Proteicos , Tauopatias/metabolismo , Tauopatias/patologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , SolubilidadeRESUMO
The brain changes of Alzheimer's disease (AD) include Abeta (Aß) amyloid plaques ("A"), abnormally phosphorylated tau tangles ("T"), and neurodegeneration ("N"). These have been used to construct in vivo and postmortem diagnostic and staging classifications for evaluating the spectrum of AD in the "ATN" and "ABC" ("B" for Braak tau stage, "C" for Consortium to Establish a Registry for Alzheimer's Disease [CERAD] neuritic plaque density) systems. Another common AD feature involves cerebral amyloid angiopathy (CAA). We report the first experiment to examine relationships among cognition, brain distribution of amyloid plaques, CAA, tau/tangles, and magnetic resonance imaging (MRI)-determined volume changes (as a measure of "N") in the same group of behaviorally characterized nonhuman primates. Both ATN and ABC systems were applied to a group of 32 rhesus macaques aged between 7 and 33 years. When an immunohistochemical method for "T" and "B" was used, some monkeys were "triple positive" on ATN, with a maximum ABC status of A1B2C3. With silver or thioflavin S methods, however, all monkeys were classified as T-negative and B0, indicating the absence of mature neurofibrillary tangles (NFTs) and hence neuropathologically defined AD. Although monkeys at extremes of the ATN and ABC classifications, or with frequent CAA, had significantly lower scores on some cognitive tests, the lack of fully mature NFTs or dementia-consistent cognitive impairment indicates that fully developed AD may not occur in rhesus macaques. There were sex differences noted in the types of histopathology present, and only CAA was significantly related to gray matter volume.
Assuntos
Envelhecimento , Doença de Alzheimer , Encéfalo , Substância Cinzenta , Macaca mulatta , Imageamento por Ressonância Magnética , Animais , Doença de Alzheimer/patologia , Doença de Alzheimer/diagnóstico por imagem , Masculino , Feminino , Imageamento por Ressonância Magnética/métodos , Envelhecimento/patologia , Envelhecimento/fisiologia , Humanos , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Encéfalo/patologia , Encéfalo/diagnóstico por imagem , Placa Amiloide/patologia , Placa Amiloide/diagnóstico por imagem , Emaranhados Neurofibrilares/patologia , Cognição/fisiologia , Transtornos Cognitivos/patologia , Transtornos Cognitivos/diagnóstico por imagem , Proteínas tau/metabolismoRESUMO
Progressive supranuclear palsy (PSP) is an incurable neurodegenerative disease characterized by 4-repeat (0N/4R)-Tau protein accumulation in CNS neurons. We generated transgenic zebrafish expressing human 0N/4R-Tau to investigate PSP pathophysiology. Tau zebrafish replicated multiple features of PSP, including: decreased survival; hypokinesia; impaired optokinetic responses; neurodegeneration; neuroinflammation; synapse loss; and Tau hyperphosphorylation, misfolding, mislocalization, insolubility, truncation, and oligomerization. Using automated assays, we screened 147 small molecules for activity in rescuing neurological deficits in Tau zebrafish. (+)JQ1, a bromodomain inhibitor, improved hypokinesia, survival, microgliosis, and brain synapse elimination. A heterozygous brd4+/- mutant reducing expression of the bromodomain protein Brd4 similarly rescued these phenotypes. Microglial phagocytosis of synaptic material was decreased by (+)JQ1 in both Tau zebrafish and rat primary cortical cultures. Microglia in human PSP brains expressed Brd4. Our findings implicate Brd4 as a regulator of microglial synaptic elimination in tauopathy and provide an unbiased approach for identifying mechanisms and therapeutic targets in PSP.
Assuntos
Animais Geneticamente Modificados , Modelos Animais de Doenças , Microglia , Paralisia Supranuclear Progressiva , Sinapses , Fatores de Transcrição , Peixe-Zebra , Proteínas tau , Animais , Humanos , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Proteínas tau/metabolismo , Proteínas tau/genética , Microglia/metabolismo , Microglia/patologia , Sinapses/metabolismo , Paralisia Supranuclear Progressiva/metabolismo , Paralisia Supranuclear Progressiva/genética , Paralisia Supranuclear Progressiva/patologia , Azepinas/farmacologia , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Triazóis/farmacologia , Ratos , Proteínas de Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética , Encéfalo/metabolismo , Encéfalo/patologia , Fagocitose , Neurônios/metabolismo , Proteínas que Contêm Bromodomínio , Proteínas de Ciclo CelularRESUMO
[18F]Flortaucipir is an FDA-approved tau-PET tracer that is increasingly utilized in clinical settings for the diagnosis of Alzheimer's disease. Still, a large-scale comparison of the in vivo PET uptake to quantitative post-mortem tau pathology and to other co-pathologies is lacking. Here, we examined the correlation between in vivo [18F]flortaucipir PET uptake and quantitative post-mortem tau pathology in corresponding brain regions from the AVID A16 end-of-life study (n = 63). All participants underwent [18F]flortaucipir PET scans prior to death, followed by a detailed post-mortem neuropathological examination using AT8 (tau) immunohistochemistry. Correlations between [18F]flortaucipir standardized uptake value ratios (SUVRs) and AT8 immunohistochemistry were assessed across 18 regions-of-interest (ROIs). To assess [18F]flortaucipir specificity and level of detection for tau pathology, correlations between [18F]flortaucipir SUVR and neuritic plaque score and TDP-43 stage were also computed and retention was further assessed in individuals with possible primary age-related tauopathy (PART), defined as Thal phase ≤ 2 and Braak stage I-IV. We found modest-to-strong correlations between in vivo [18F]flortaucipir SUVR and post-mortem tau pathology density in corresponding brain regions in all neocortical regions analyzed (rho-range = 0.61-0.79, p < 0.0001 for all). The detection threshold of [18F]flortaucipir PET was determined to be 0.85% of surface area affected by tau pathology in a temporal meta-ROI, and 0.15% in a larger cortical meta-ROI. No significant associations were found between [18F]flortaucipir SUVRs and post-mortem tau pathology in individuals with possible PART. Further, there was no correlation observed between [18F]flortaucipir and level of amyloid-ß neuritic plaque load (rho-range = - 0.16-0.12; p = 0.48-0.61) or TDP-43 stage (rho-range = - 0.10 to - 0.30; p = 0.18-0.65). In conclusion, our in vivo vs post-mortem study shows that the in vivo [18F]flortaucipir PET signal primarily reflects tau pathology, also at relatively low densities of tau proteinopathy, and does not bind substantially to tau neurites in neuritic plaques or in individuals with PART.
Assuntos
Encéfalo , Carbolinas , Tomografia por Emissão de Pósitrons , Proteínas tau , Humanos , Proteínas tau/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Feminino , Encéfalo/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Masculino , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Compostos Radiofarmacêuticos , Radioisótopos de FlúorRESUMO
The molecular pathogenesis of Alzheimer's disease (AD) has been elucidated through the biochemical analysis of senile plaques, neurofibrillary tangles, and pathological features of the brains of patients with AD. Genetic analysis, initiated with familial AD investigation, has revealed that Aß aggregation and accumulation are crucial processes in AD pathogenesis. The success of lecanemab against aggregated Aß is the result of these efforts. Meanwhile, research on tau as a causative molecule in AD and various other tauopathies is advancing gradually. Furthermore, genetic analysis has revealed that the inflammatory response of glial cells modifies AD pathophysiology; a novel therapeutic strategy for inflammation control is thus currently under consideration. This article summarizes the latest discoveries related to these new therapeutic strategies for AD.
Assuntos
Doença de Alzheimer , Proteínas tau , Animais , Humanos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/imunologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/imunologia , Peptídeos beta-Amiloides/metabolismo , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/metabolismo , Proteínas tau/imunologia , Proteínas tau/metabolismoRESUMO
Preventative treatment for Alzheimer's Disease (AD) is dire, yet mechanisms underlying early regional vulnerability remain unknown. In AD, one of the earliest pathophysiological correlates to cognitive decline is hyperexcitability, which is observed first in the entorhinal cortex. Why hyperexcitability preferentially emerges in specific regions in AD is unclear. Using regional, cell-type-specific proteomics and electrophysiology in wild-type mice, we uncovered a unique susceptibility of the entorhinal cortex to human amyloid precursor protein (hAPP). Entorhinal hyperexcitability resulted from selective vulnerability of parvalbumin (PV) interneurons, with respect to surrounding excitatory neurons. This effect was partially replicated with an APP chimera containing a humanized amyloid-beta sequence. EC hyperexcitability could be ameliorated by co-expression of human Tau with hAPP at the expense of increased pathological tau species, or by enhancing PV interneuron excitability in vivo. This study suggests early interventions targeting inhibitory neurons may protect vulnerable regions from the effects of APP/amyloid and tau pathology.
Assuntos
Doença de Alzheimer , Precursor de Proteína beta-Amiloide , Córtex Entorrinal , Interneurônios , Proteínas tau , Animais , Feminino , Humanos , Masculino , Camundongos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Precursor de Proteína beta-Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Modelos Animais de Doenças , Córtex Entorrinal/metabolismo , Córtex Entorrinal/patologia , Interneurônios/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Parvalbuminas/metabolismo , Proteínas tau/metabolismo , Proteínas tau/genéticaRESUMO
Microtubule-associated protein tau (MAPT/tau) accumulates in a family of neurodegenerative diseases, including Alzheimer's disease (AD). In disease, tau is aberrantly modified by post-translational modifications (PTMs), including hyper-phosphorylation. However, it is often unclear which of these PTMs contribute to tau's accumulation or what mechanisms might be involved. To explore these questions, we focus on a cleaved proteoform of tau (tauC3), which selectively accumulates in AD and was recently shown to be degraded by its direct binding to the E3 ubiquitin ligase, CHIP. Here, we find that phosphorylation of tauC3 at a single residue, pS416, is sufficient to weaken its interaction with CHIP. A co-crystal structure of CHIP bound to the C-terminus of tauC3 reveals the mechanism of this clash, allowing design of a mutation (CHIPD134A) that partially restores binding and turnover of pS416 tauC3. We confirm that, in our models, pS416 is produced by the known AD-associated kinase, MARK2/Par-1b, providing a potential link to disease. In further support of this idea, an antibody against pS416 co-localizes with tauC3 in degenerative neurons within the hippocampus of AD patients. Together, these studies suggest a molecular mechanism for how phosphorylation at a discrete site contributes to accumulation of a tau proteoform.
Assuntos
Doença de Alzheimer , Ligação Proteica , Ubiquitina-Proteína Ligases , Proteínas tau , Proteínas tau/metabolismo , Proteínas tau/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/química , Fosforilação , Humanos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/genética , Animais , Células HEK293 , Cristalografia por Raios X , Processamento de Proteína Pós-TraducionalRESUMO
BACKGROUND: The medial temporal lobe (MTL) is hypothesized to be relatively spared in early-onset Alzheimer's disease (EOAD). Yet, detailed examination of MTL subfields and drivers of atrophy in amnestic EOAD is lacking. METHODS: BioFINDER-2 participants with memory impairment, abnormal amyloid-ß and tau-PET were included. Forty-one amnestic EOAD individuals ≤65 years and, as comparison, late-onset AD (aLOAD, ≥70 years, n = 154) and amyloid-ß-negative cognitively unimpaired controls were included. MTL subregions and biomarkers of (co-)pathologies were measured. RESULTS: AD groups showed smaller MTL subregions compared to controls. Atrophy patterns were similar across AD groups: aLOAD showed thinner entorhinal cortices than aEOAD; aEOAD showed thinner parietal regions than aLOAD. aEOAD showed lower white matter hyperintensities than aLOAD. No differences in MTL tau-PET or transactive response DNA binding protein 43-proxy positivity were found. CONCLUSIONS: We found evidence for MTL atrophy in amnestic EOAD and overall similar levels to aLOAD of MTL tau pathology and co-pathologies.
Assuntos
Doença de Alzheimer , Atrofia , Tomografia por Emissão de Pósitrons , Lobo Temporal , Humanos , Doença de Alzheimer/patologia , Doença de Alzheimer/diagnóstico por imagem , Atrofia/patologia , Masculino , Feminino , Idoso , Lobo Temporal/patologia , Lobo Temporal/diagnóstico por imagem , Pessoa de Meia-Idade , Imageamento por Ressonância Magnética , Proteínas tau/metabolismo , Idade de Início , Peptídeos beta-Amiloides/metabolismo , Amnésia/patologia , Amnésia/diagnóstico por imagem , Idoso de 80 Anos ou maisRESUMO
Tauopathies, including Alzheimer's disease, corticobasal degeneration and progressive supranuclear palsy, are characterised by the aggregation of tau into insoluble neurofibrillary tangles in the brain. Tau is subject to a range of post-translational modifications, including proteolysis, that can promote its aggregation. Neuroinflammation is a hallmark of tauopathies and evidence is growing for a role of CD8+ T cells in disease pathogenesis. CD8+ T cells release granzyme proteases but what role these proteases play in neuronal dysfunction is currently lacking. Here, we identified that granzyme A (GzmA) is present in brain tissue and proteolytically cleaves tau. Mass spectrometric analysis of tau fragments produced on digestion of tau with GzmA identified three cleavage sites at R194-S195, R209-S210 and K240-S241. Mutation of the critical Arg or Lys residues at the cleavage sites in tau or chemical inhibition of GzmA blocked the proteolysis of tau by GzmA. Development of a semi-targeted mass spectrometry approach identified peptides in tauopathy brain tissue corresponding to proteolysis by GzmA at R209-S210 and K240-S241 in tau. When expressed in cells the GzmA-cleaved C-terminal fragments of tau were highly phosphorylated and aggregated upon incubation of the cells with tauopathy brain seed. The C-terminal fragment tau195-441 was able to transfer between cells and promote aggregation of tau in acceptor cells, indicating the propensity for such tau fragments to propagate between cells. Collectively, these results raise the possibility that GzmA, released from infiltrating cytotoxic CD8+ T cells, proteolytically cleaves tau into fragments that may contribute to its pathological properties in tauopathies.
Assuntos
Granzimas , Proteólise , Tauopatias , Proteínas tau , Humanos , Proteínas tau/metabolismo , Proteínas tau/genética , Granzimas/metabolismo , Granzimas/genética , Tauopatias/metabolismo , Tauopatias/patologia , Tauopatias/genética , Encéfalo/metabolismo , Encéfalo/patologia , Linfócitos T CD8-Positivos/metabolismo , Agregação Patológica de Proteínas/metabolismo , Agregação Patológica de Proteínas/genéticaRESUMO
Neurodegenerative diseases (NDDs) are a diverse group of neurological disorders characterized by alterations in the structure and function of the central nervous system. Alzheimer's disease (AD), characterized by impaired memory and cognitive abilities, is the most prevalent type of senile dementia. Loss of synapses, intracellular aggregation of hyperphosphorylated tau protein, and extracellular amyloid-ß peptide (Aß) plaques are the hallmarks of AD. MicroRNAs (miRNAs/miRs) are single-stranded ribonucleic acid (RNA) molecules that bind to the 3' and 5' untranslated regions of target genes to cause post-transcriptional gene silencing. The brain expresses over 70% of all experimentally detected miRNAs, and these miRNAs are crucial for synaptic function and particular signals during memory formation. Increasing evidence suggests that miRNAs play a role in AD pathogenesis and we provide an overview of the role of miRNAs in synapse formation, Aß synthesis, tau protein accumulation, and brain-derived neurotrophic factor-associated AD pathogenesis. We further summarize and discuss the role of miRNAs as potential therapeutic targets and biomarkers for AD detection and differentiation between early- and late-stage AD, based on recent research. In conclusion, altered expression of miRNAs in the brain and peripheral circulation demonstrates their potential as biomarkers and therapeutic targets in AD.
Assuntos
Doença de Alzheimer , Biomarcadores , MicroRNAs , Doença de Alzheimer/genética , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/terapia , Humanos , MicroRNAs/genética , Proteínas tau/metabolismo , Proteínas tau/genética , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/genética , Animais , Prognóstico , Encéfalo/metabolismo , Encéfalo/patologiaRESUMO
Alzheimer's disease (AD) is characterized by the accumulation of amyloid-beta plaques initiated approximately 2 decades before the symptom onset followed by build-up and spreading of neurofibrillary tau aggregates. Although it has been suggested that the amyloid-beta amplifies tau spreading the observed spatial disparity called it into question. Yet, it is unclear how neocortical amyloid-beta remotely affects early pathological tau, triggering it to leave the early formation area, and how amyloid-beta facilitates tau aggregate spreading throughout cortical regions. I aimed to investigate how amyloid-beta can facilitate tau spreading through neuronal connections in the Alzheimer's disease pathological process by combining functional magnetic resonance imaging normative connectomes and longitudinal in vivo molecular imaging data. In total, the imaging data of 317 participants, including 173 amyloid-beta-negative non-demented and 144 amyloid-beta -positive non-demented participants, have entered the study from Alzheimer's Disease Neuroimaging Initiative. Furthermore, normative resting-state functional magnetic resonance imaging connectomes were used to model tau spreading through functional connections. It was observed that the amyloid-beta in regions with the highest deposition (amyloid-beta epicenter) is remotely associated with connectivity-based spreading of tau pathology. Moreover, amyloid-beta in regions that exhibit the highest tau pathology (tau epicenter) is associated with increased connectivity-based tau spreading to non-epicenter regions. The findings provide a further explanation for a long-standing question of how amyloid-beta can affect tau aggregate spreading through neuronal connections despite spatial incongruity. The results suggest that amyloid-beta pathology can remotely and locally facilitate connectivity-based spreading of tau aggregates.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Imageamento por Ressonância Magnética , Proteínas tau , Humanos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Proteínas tau/metabolismo , Feminino , Masculino , Idoso , Peptídeos beta-Amiloides/metabolismo , Imageamento por Ressonância Magnética/métodos , Conectoma , Idoso de 80 Anos ou mais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/patologia , Pessoa de Meia-IdadeRESUMO
BACKGROUND AND OBJECTIVES: Alzheimer disease (AD) is associated with a 2 to 3-fold increased risk of developing late-onset focal epilepsy, yet it remains unclear how development of focal epilepsy in AD is related to AD pathology. The objective of this study was to examine spatial relationships between the epileptogenic zone and tau deposition, amyloid deposition, and brain atrophy in individuals with AD who developed late-onset, otherwise unexplained focal epilepsy. We hypothesized that if network hyperexcitability is mechanistically linked to AD pathology, then there would be increased tau and amyloid deposition within the epileptogenic hemisphere. METHODS: In this cross-sectional study, we performed tau and amyloid PET imaging, brain MRI, and overnight scalp EEG in individuals with early clinical stages of AD who developed late-onset, otherwise unexplained focal epilepsy (AD-Ep). Participants were referred from epilepsy and memory disorders clinics at our institutions. We determined epilepsy localization based on EEG findings and seizure semiology. We quantified tau deposition, amyloid deposition, and atrophy across brain regions and calculated asymmetry indices for these measures. We compared findings in AD-Ep with those in a control AD group without epilepsy (AD-NoEp). RESULTS: The AD-Ep group included 8 individuals with a mean age of 69.5 ± 4.2 years at PET imaging. The AD-NoEp group included 14 individuals with a mean age of 71.7 ± 9.8 years at PET imaging. In AD-Ep, we found a highly asymmetric pattern of tau deposition, with significantly greater tau in the epileptogenic hemisphere. Amyloid deposition and cortical atrophy were also greater in the epileptogenic hemisphere, although the magnitudes of asymmetry were reduced compared with tau. Compared with AD-NoEp, the AD-Ep group had significantly greater tau asymmetry and trends toward greater asymmetry of amyloid and atrophy. AD-Ep also had significantly greater amyloid burden bilaterally and trends toward greater tau burden within the epileptogenic hemisphere, compared with AD-NoEp. DISCUSSION: Our results reveal a spatial association between the epileptogenic focus and tau deposition, amyloid deposition, and neurodegeneration in early clinical stages of AD. Within the limitations of a cross-sectional study with small sample sizes, these findings contribute to our understanding of the clinicopathologic heterogeneity of AD, demonstrating an association between focal epilepsy and lateralized pathology in AD.