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1.
Cell ; 185(13): 2213-2233.e25, 2022 06 23.
Artículo en Inglés | MEDLINE | ID: mdl-35750033

RESUMEN

The impact of apolipoprotein E ε4 (APOE4), the strongest genetic risk factor for Alzheimer's disease (AD), on human brain cellular function remains unclear. Here, we investigated the effects of APOE4 on brain cell types derived from population and isogenic human induced pluripotent stem cells, post-mortem brain, and APOE targeted replacement mice. Population and isogenic models demonstrate that APOE4 local haplotype, rather than a single risk allele, contributes to risk. Global transcriptomic analyses reveal human-specific, APOE4-driven lipid metabolic dysregulation in astrocytes and microglia. APOE4 enhances de novo cholesterol synthesis despite elevated intracellular cholesterol due to lysosomal cholesterol sequestration in astrocytes. Further, matrisome dysregulation is associated with upregulated chemotaxis, glial activation, and lipid biosynthesis in astrocytes co-cultured with neurons, which recapitulates altered astrocyte matrisome signaling in human brain. Thus, APOE4 initiates glia-specific cell and non-cell autonomous dysregulation that may contribute to increased AD risk.


Asunto(s)
Enfermedad de Alzheimer , Células Madre Pluripotentes Inducidas , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Animales , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Astrocitos/metabolismo , Colesterol/metabolismo , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Ratones , Microglía/metabolismo
2.
Cell ; 184(17): 4547-4563.e17, 2021 08 19.
Artículo en Inglés | MEDLINE | ID: mdl-34314701

RESUMEN

Frontotemporal dementia (FTD) because of MAPT mutation causes pathological accumulation of tau and glutamatergic cortical neuronal death by unknown mechanisms. We used human induced pluripotent stem cell (iPSC)-derived cerebral organoids expressing tau-V337M and isogenic corrected controls to discover early alterations because of the mutation that precede neurodegeneration. At 2 months, mutant organoids show upregulated expression of MAPT, glutamatergic signaling pathways, and regulators, including the RNA-binding protein ELAVL4, and increased stress granules. Over the following 4 months, mutant organoids accumulate splicing changes, disruption of autophagy function, and build-up of tau and P-tau-S396. By 6 months, tau-V337M organoids show specific loss of glutamatergic neurons as seen in individuals with FTD. Mutant neurons are susceptible to glutamate toxicity, which can be rescued pharmacologically by the PIKFYVE kinase inhibitor apilimod. Our results demonstrate a sequence of events that precede neurodegeneration, revealing molecular pathways associated with glutamate signaling as potential targets for therapeutic intervention in FTD.


Asunto(s)
Cerebro/patología , Proteína 4 Similar a ELAV/genética , Ácido Glutámico/metabolismo , Mutación/genética , Neuronas/patología , Organoides/metabolismo , Empalme del ARN/genética , Proteínas tau/genética , Autofagia/efectos de los fármacos , Autofagia/genética , Biomarcadores/metabolismo , Tipificación del Cuerpo/efectos de los fármacos , Tipificación del Cuerpo/genética , Muerte Celular/efectos de los fármacos , Línea Celular , Humanos , Hidrazonas/farmacología , Lisosomas/efectos de los fármacos , Lisosomas/metabolismo , Morfolinas/farmacología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Organoides/efectos de los fármacos , Organoides/ultraestructura , Fosforilación/efectos de los fármacos , Pirimidinas/farmacología , Empalme del ARN/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Gránulos de Estrés/efectos de los fármacos , Gránulos de Estrés/metabolismo , Sinapsis/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genética
3.
Nature ; 611(7936): 585-593, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-36352225

RESUMEN

Macrophages are important players in the maintenance of tissue homeostasis1. Perivascular and leptomeningeal macrophages reside near the central nervous system (CNS) parenchyma2, and their role in CNS physiology has not been sufficiently well studied. Given their continuous interaction with the cerebrospinal fluid (CSF) and strategic positioning, we refer to these cells collectively as parenchymal border macrophages (PBMs). Here we demonstrate that PBMs regulate CSF flow dynamics. We identify a subpopulation of PBMs that express high levels of CD163 and LYVE1 (scavenger receptor proteins), closely associated with the brain arterial tree, and show that LYVE1+ PBMs regulate arterial motion that drives CSF flow. Pharmacological or genetic depletion of PBMs led to accumulation of extracellular matrix proteins, obstructing CSF access to perivascular spaces and impairing CNS perfusion and clearance. Ageing-associated alterations in PBMs and impairment of CSF dynamics were restored after intracisternal injection of macrophage colony-stimulating factor. Single-nucleus RNA sequencing data obtained from patients with Alzheimer's disease (AD) and from non-AD individuals point to changes in phagocytosis, endocytosis and interferon-γ signalling on PBMs, pathways that are corroborated in a mouse model of AD. Collectively, our results identify PBMs as new cellular regulators of CSF flow dynamics, which could be targeted pharmacologically to alleviate brain clearance deficits associated with ageing and AD.


Asunto(s)
Sistema Nervioso Central , Líquido Cefalorraquídeo , Macrófagos , Tejido Parenquimatoso , Animales , Ratones , Enfermedad de Alzheimer/metabolismo , Encéfalo/metabolismo , Sistema Nervioso Central/citología , Sistema Nervioso Central/metabolismo , Líquido Cefalorraquídeo/metabolismo , Macrófagos/fisiología , Meninges/citología , Reología , Proteínas de la Matriz Extracelular/metabolismo , Envejecimiento/metabolismo , Fagocitosis , Endocitosis , Interferón gamma/metabolismo , Tejido Parenquimatoso/citología , Humanos
4.
PLoS Biol ; 22(4): e3002607, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38687811

RESUMEN

Unbiased data-driven omic approaches are revealing the molecular heterogeneity of Alzheimer disease. Here, we used machine learning approaches to integrate high-throughput transcriptomic, proteomic, metabolomic, and lipidomic profiles with clinical and neuropathological data from multiple human AD cohorts. We discovered 4 unique multimodal molecular profiles, one of them showing signs of poor cognitive function, a faster pace of disease progression, shorter survival with the disease, severe neurodegeneration and astrogliosis, and reduced levels of metabolomic profiles. We found this molecular profile to be present in multiple affected cortical regions associated with higher Braak tau scores and significant dysregulation of synapse-related genes, endocytosis, phagosome, and mTOR signaling pathways altered in AD early and late stages. AD cross-omics data integration with transcriptomic data from an SNCA mouse model revealed an overlapping signature. Furthermore, we leveraged single-nuclei RNA-seq data to identify distinct cell-types that most likely mediate molecular profiles. Lastly, we identified that the multimodal clusters uncovered cerebrospinal fluid biomarkers poised to monitor AD progression and possibly cognition. Our cross-omics analyses provide novel critical molecular insights into AD.


Asunto(s)
Enfermedad de Alzheimer , Encéfalo , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Humanos , Animales , Encéfalo/metabolismo , Encéfalo/patología , Ratones , Transcriptoma/genética , Proteómica/métodos , Masculino , Biomarcadores/metabolismo , Metabolómica/métodos , Aprendizaje Automático , Femenino , Progresión de la Enfermedad , Anciano , Modelos Animales de Enfermedad , Multiómica
5.
Nature ; 593(7858): 255-260, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33911285

RESUMEN

Alzheimer's disease (AD) is the most prevalent cause of dementia1. Although there is no effective treatment for AD, passive immunotherapy with monoclonal antibodies against amyloid beta (Aß) is a promising therapeutic strategy2,3. Meningeal lymphatic drainage has an important role in the accumulation of Aß in the brain4, but it is not known whether modulation of meningeal lymphatic function can influence the outcome of immunotherapy in AD. Here we show that ablation of meningeal lymphatic vessels in 5xFAD mice (a mouse model of amyloid deposition that expresses five mutations found in familial AD) worsened the outcome of mice treated with anti-Aß passive immunotherapy by exacerbating the deposition of Aß, microgliosis, neurovascular dysfunction, and behavioural deficits. By contrast, therapeutic delivery of vascular endothelial growth factor C improved clearance of Aß by monoclonal antibodies. Notably, there was a substantial overlap between the gene signature of microglia from 5xFAD mice with impaired meningeal lymphatic function and the transcriptional profile of activated microglia from the brains of individuals with AD. Overall, our data demonstrate that impaired meningeal lymphatic drainage exacerbates the microglial inflammatory response in AD and that enhancement of meningeal lymphatic function combined with immunotherapies could lead to better clinical outcomes.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/inmunología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Inmunoterapia , Vasos Linfáticos/inmunología , Meninges/inmunología , Microglía/inmunología , Envejecimiento/efectos de los fármacos , Envejecimiento/inmunología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/efectos de los fármacos , Animales , Anticuerpos Monoclonales Humanizados/inmunología , Encéfalo/irrigación sanguínea , Encéfalo/citología , Encéfalo/efectos de los fármacos , Encéfalo/inmunología , Modelos Animales de Enfermedad , Hipocampo/citología , Hipocampo/efectos de los fármacos , Hipocampo/inmunología , Humanos , Inflamación/tratamiento farmacológico , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Masculino , Meninges/irrigación sanguínea , Meninges/citología , Ratones , Microglía/citología , Microglía/efectos de los fármacos , Transcripción Genética/efectos de los fármacos , Factor C de Crecimiento Endotelial Vascular/metabolismo , Factor C de Crecimiento Endotelial Vascular/farmacología
6.
J Neurosci ; 44(24)2024 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-38649269

RESUMEN

Genetic variants in the apolipoprotein E (APOE) gene affect the onset and progression of Alzheimer's disease (AD). The APOE Christchurch (APOE Ch) variant has been identified as the most prominent candidate for preventing the onset and progression of AD. In this study, we generated isogenic APOE3Ch/3Ch human-induced pluripotent stem cells (iPSCs) from APOE3/3 healthy control female iPSCs and induced them into astrocytes. RNA expression analysis revealed the inherent resilience of APOE3Ch/3Ch astrocytes to induce a reactive state in response to inflammatory cytokines. Moreover, cytokine treatment changed astrocytic morphology with more complexity in APOE3/3 astrocytes, but not in APOE3Ch/3Ch astrocytes, indicating resilience of the rare variant to a reactive state. Interestingly, we observed robust morphological alterations containing more intricate processes when cocultured with iPSC-derived cortical neurons, in which APOE3Ch/3Ch astrocytes reduced complexity compared with APOE3/3 astrocytes. To assess the impacts of tau propagation effects, we next developed a sophisticated and sensitive assay utilizing cortical neurons derived from human iPSCs, previously generated from donors of both sexes. We showed that APOE3Ch/3Ch astrocytes effectively mitigated tau propagation within iPSC-derived neurons. This study provides important experimental evidence of the characteristic functions exhibited by APOE3Ch/3Ch astrocytes, thereby offering valuable insights for the advancement of novel clinical interventions in AD research.


Asunto(s)
Astrocitos , Células Madre Pluripotentes Inducidas , Proteínas tau , Astrocitos/metabolismo , Humanos , Proteínas tau/metabolismo , Proteínas tau/genética , Femenino , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Apolipoproteína E3/genética , Neuronas/metabolismo , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Células Cultivadas , Técnicas de Cocultivo
7.
Stem Cells ; 42(2): 107-115, 2024 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-37995336

RESUMEN

Advanced technologies have enabled the engineering of self-organized 3-dimensional (3D) cellular structures from human induced pluripotent stem cells (hiPSCs), namely organoids, which recapitulate some key features of tissue development and functions of the human central nervous system (CNS). While hiPSC-derived 3D CNS organoids hold promise in providing a human-specific platform for studying CNS development and diseases, most of them do not incorporate the full range of implicated cell types, including vascular cell components and microglia, limiting their ability to accurately recreate the CNS environment and their utility in the study of certain aspects of the disease. Here we have developed a novel approach, called vascularized brain assembloids, for constructing hiPSC-derived 3D CNS structures with a higher level of cellular complexity. This is achieved by integrating forebrain organoids with common myeloid progenitors and phenotypically stabilized human umbilical vein endothelial cells (VeraVecs), which can be cultured and expanded in serum-free conditions. Compared with organoids, these assembloids exhibited enhanced neuroepithelial proliferation, advanced astrocytic maturation, and increased synapse numbers. Strikingly, the assembloids derived from hiPSCs harboring the tauP301S mutation exhibited increased levels of total tau and phosphorylated tau, along with a higher proportion of rod-like microglia-like cells and enhanced astrocytic activation, when compared to the assembloids derived from isogenic hiPSCs. Additionally, the tauP301S assembloids showed an altered profile of neuroinflammatory cytokines. This innovative assembloid technology serves as a compelling proof-of-concept model, opening new avenues for unraveling the intricate complexities of the human brain and accelerating progress in the development of effective treatments for neurological disorders.


Asunto(s)
Células Madre Pluripotentes Inducidas , Tauopatías , Humanos , Encéfalo , Sistema Nervioso Central , Organoides , Células Endoteliales de la Vena Umbilical Humana
8.
Mol Cell Neurosci ; 130: 103954, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39032719

RESUMEN

BACKGROUND: Tau post-translational modifications (PTMs) result in the gradual build-up of abnormal tau and neuronal degeneration in tauopathies, encompassing variants of frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). Tau proteolytically cleaved by active caspases, including caspase-6, may be neurotoxic and prone to self-aggregation. Also, our recent findings show that caspase-6 truncated tau represents a frequent and understudied aspect of tau pathology in AD in addition to phospho-tau pathology. In AD and Pick's disease, a large percentage of caspase-6 associated cleaved-tau positive neurons lack phospho-tau, suggesting that many vulnerable neurons to tau pathology go undetected when using conventional phospho-tau antibodies and possibly will not respond to phospho-tau based therapies. Therefore, therapeutic strategies against caspase cleaved-tau pathology could be necessary to modulate the extent of tau abnormalities in AD and other tauopathies. METHODS: To understand the timing and progression of caspase activation, tau cleavage, and neuronal death, we created two mAbs targeting caspase-6 tau cleavage sites and probed postmortem brain tissue from an individual with FTLD due to the V337M MAPT mutation. We then assessed tau cleavage and apoptotic stress response in cortical neurons derived from induced pluripotent stem cells (iPSCs) carrying the FTD-related V337M MAPT mutation. Finally, we evaluated the neuroprotective effects of caspase inhibitors in these iPSC-derived neurons. RESULTS: FTLD V337M MAPT postmortem brain showed positivity for both cleaved tau mAbs and active caspase-6. Relative to isogenic wild-type MAPT controls, V337M MAPT neurons cultured for 3 months post-differentiation showed a time-dependent increase in pathogenic tau in the form of caspase-cleaved tau, phospho-tau, and higher levels of tau oligomers. Accumulation of toxic tau species in V337M MAPT neurons was correlated with increased vulnerability to pro-apoptotic stress. Notably, this mutation-associated cell death was pharmacologically rescued by the inhibition of effector caspases. CONCLUSIONS: Our results suggest an upstream, time-dependent accumulation of caspase-6 cleaved tau in V337M MAPT neurons promoting neurotoxicity. These processes can be reversed by caspase inhibition. These results underscore the potential of developing caspase-6 inhibitors as therapeutic agents for FTLD and other tauopathies. Additionally, they highlight the promise of using caspase-cleaved tau as biomarkers for these conditions.


Asunto(s)
Apoptosis , Caspasa 6 , Células Madre Pluripotentes Inducidas , Neuronas , Proteínas tau , Proteínas tau/metabolismo , Proteínas tau/genética , Células Madre Pluripotentes Inducidas/metabolismo , Neuronas/metabolismo , Apoptosis/genética , Humanos , Caspasa 6/metabolismo , Caspasa 6/genética , Mutación/genética , Células Cultivadas , Tauopatías/metabolismo , Tauopatías/genética , Tauopatías/patología
9.
Ann Neurol ; 93(6): 1158-1172, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-36843330

RESUMEN

OBJECTIVE: Identifying cerebrospinal fluid measures of the microtubule binding region of tau (MTBR-tau) species that reflect tau aggregation could provide fluid biomarkers that track Alzheimer's disease related neurofibrillary tau pathological changes. We examined the cerebrospinal fluid (CSF) MTBR-tau species in dominantly inherited Alzheimer's disease (DIAD) mutation carriers to assess the association with Alzheimer's disease (AD) biomarkers and clinical symptoms. METHODS: Cross-sectional and longitudinal CSF from 229 DIAD mutation carriers and 130 mutation non-carriers had sequential characterization of N-terminal/mid-domain phosphorylated tau (p-tau) followed by MTBR-tau species and tau positron emission tomography (tau PET), other soluble tau and amyloid biomarkers, comprehensive clinical and cognitive assessments, and brain magnetic resonance imaging of atrophy. RESULTS: CSF MTBR-tau species located within the putative "border" region and one species corresponding to the "core" region of aggregates in neurofibrillary tangles (NFTs) increased during the presymptomatic stage and decreased during the symptomatic stage. The "border" MTBR-tau species were associated with amyloid pathology and CSF p-tau; whereas the "core" MTBR-tau species were associated stronger with tau PET and CSF measures of neurodegeneration. The ratio of the border to the core species provided a continuous measure of increasing amounts that tracked clinical progression and NFTs. INTERPRETATION: Changes in CSF soluble MTBR-tau species preceded the onset of dementia, tau tangle increase, and atrophy in DIAD. The ratio of 4R-specific MTBR-tau (border) to the NFT (core) MTBR-tau species corresponds to the pathology of NFTs in DIAD and change with disease progression. The dynamics between different MTBR-tau species in the CSF may serve as a marker of tau-related disease progression and target engagement of anti-tau therapeutics. ANN NEUROL 2023;93:1158-1172.


Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Estudios Transversales , Proteínas tau/metabolismo , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/genética , Disfunción Cognitiva/líquido cefalorraquídeo , Péptidos beta-Amiloides/metabolismo , Tomografía de Emisión de Positrones/métodos , Atrofia/patología , Biomarcadores/líquido cefalorraquídeo , Progresión de la Enfermedad , Microtúbulos/metabolismo , Microtúbulos/patología
10.
Mol Psychiatry ; 28(11): 4889-4901, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37730840

RESUMEN

Tauopathies are a heterogenous group of neurodegenerative disorders characterized by tau aggregation in the brain. In a subset of tauopathies, rare mutations in the MAPT gene, which encodes the tau protein, are sufficient to cause disease; however, the events downstream of MAPT mutations are poorly understood. Here, we investigate the role of long non-coding RNAs (lncRNAs), transcripts >200 nucleotides with low/no coding potential that regulate transcription and translation, and their role in tauopathy. Using stem cell derived neurons from patients carrying a MAPT p.P301L, IVS10 + 16, or p.R406W mutation and CRISPR-corrected isogenic controls, we identified transcriptomic changes that occur as a function of the MAPT mutant allele. We identified 15 lncRNAs that were commonly differentially expressed across the three MAPT mutations. The commonly differentially expressed lncRNAs interact with RNA-binding proteins that regulate stress granule formation. Among these lncRNAs, SNHG8 was significantly reduced in a mouse model of tauopathy and in FTLD-tau, progressive supranuclear palsy, and Alzheimer's disease brains. We show that SNHG8 interacts with tau and stress granule-associated RNA-binding protein TIA1. Overexpression of mutant tau in vitro is sufficient to reduce SNHG8 expression and induce stress granule formation. Rescuing SNHG8 expression leads to reduced stress granule formation and reduced TIA1 levels in immortalized cells and in MAPT mutant neurons, suggesting that dysregulation of this non-coding RNA is a causal factor driving stress granule formation via TIA1 in tauopathies.


Asunto(s)
Enfermedad de Alzheimer , ARN Largo no Codificante , Tauopatías , Animales , Humanos , Ratones , Enfermedad de Alzheimer/metabolismo , Neuronas/metabolismo , ARN Largo no Codificante/genética , Gránulos de Estrés , Proteínas tau/genética , Proteínas tau/metabolismo , Tauopatías/genética , Tauopatías/metabolismo
11.
Brain ; 146(7): 2928-2943, 2023 07 03.
Artículo en Inglés | MEDLINE | ID: mdl-36625756

RESUMEN

Neurofilament light chain, a putative measure of neuronal damage, is measurable in blood and CSF and is predictive of cognitive function in individuals with Alzheimer's disease. There has been limited prior work linking neurofilament light and functional connectivity, and no prior work has investigated neurofilament light associations with functional connectivity in autosomal dominant Alzheimer's disease. Here, we assessed relationships between blood neurofilament light, cognition, and functional connectivity in a cross-sectional sample of 106 autosomal dominant Alzheimer's disease mutation carriers and 76 non-carriers. We employed an innovative network-level enrichment analysis approach to assess connectome-wide associations with neurofilament light. Neurofilament light was positively correlated with deterioration of functional connectivity within the default mode network and negatively correlated with connectivity between default mode network and executive control networks, including the cingulo-opercular, salience, and dorsal attention networks. Further, reduced connectivity within the default mode network and between the default mode network and executive control networks was associated with reduced cognitive function. Hierarchical regression analysis revealed that neurofilament levels and functional connectivity within the default mode network and between the default mode network and the dorsal attention network explained significant variance in cognitive composite scores when controlling for age, sex, and education. A mediation analysis demonstrated that functional connectivity within the default mode network and between the default mode network and dorsal attention network partially mediated the relationship between blood neurofilament light levels and cognitive function. Our novel results indicate that blood estimates of neurofilament levels correspond to direct measurements of brain dysfunction, shedding new light on the underlying biological processes of Alzheimer's disease. Further, we demonstrate how variation within key brain systems can partially mediate the negative effects of heightened total serum neurofilament levels, suggesting potential regions for targeted interventions. Finally, our results lend further evidence that low-cost and minimally invasive blood measurements of neurofilament may be a useful marker of brain functional connectivity and cognitive decline in Alzheimer's disease.


Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Conectoma , Humanos , Estudios Transversales , Filamentos Intermedios , Imagen por Resonancia Magnética/métodos , Encéfalo/diagnóstico por imagen , Cognición , Red Nerviosa/diagnóstico por imagen
12.
Alzheimers Dement ; 20(3): 2240-2261, 2024 03.
Artículo en Inglés | MEDLINE | ID: mdl-38170841

RESUMEN

INTRODUCTION: The pace of innovation has accelerated in virtually every area of tau research in just the past few years. METHODS: In February 2022, leading international tau experts convened to share selected highlights of this work during Tau 2022, the second international tau conference co-organized and co-sponsored by the Alzheimer's Association, CurePSP, and the Rainwater Charitable Foundation. RESULTS: Representing academia, industry, and the philanthropic sector, presenters joined more than 1700 registered attendees from 59 countries, spanning six continents, to share recent advances and exciting new directions in tau research. DISCUSSION: The virtual meeting provided an opportunity to foster cross-sector collaboration and partnerships as well as a forum for updating colleagues on research-advancing tools and programs that are steadily moving the field forward.


Asunto(s)
Enfermedad de Alzheimer , Tauopatías , Humanos , Proteínas tau
13.
Alzheimers Dement ; 20(6): 4351-4365, 2024 06.
Artículo en Inglés | MEDLINE | ID: mdl-38666355

RESUMEN

INTRODUCTION: Amyloid beta and tau pathology are the hallmarks of sporadic Alzheimer's disease (AD) and autosomal dominant AD (ADAD). However, Lewy body pathology (LBP) is found in ≈ 50% of AD and ADAD brains. METHODS: Using an α-synuclein seed amplification assay (SAA) in cerebrospinal fluid (CSF) from asymptomatic (n = 26) and symptomatic (n = 27) ADAD mutation carriers, including 12 with known neuropathology, we investigated the timing of occurrence and prevalence of SAA positive reactivity in ADAD in vivo. RESULTS: No asymptomatic participant and only 11% (3/27) of the symptomatic patients tested SAA positive. Neuropathology revealed LBP in 10/12 cases, primarily affecting the amygdala or the olfactory areas. In the latter group, only the individual with diffuse LBP reaching the neocortex showed α-synuclein seeding activity in CSF in vivo. DISCUSSION: Results suggest that in ADAD LBP occurs later than AD pathology and often as amygdala- or olfactory-predominant LBP, for which CSF α-synuclein SAA has low sensitivity. HIGHLIGHTS: Cerebrospinal fluid (CSF) real-time quaking-induced conversion (RT-QuIC) detects misfolded α-synuclein in ≈ 10% of symptomatic autosomal dominant Alzheimer's disease (ADAD) patients. CSF RT-QuIC does not detect α-synuclein seeding activity in asymptomatic mutation carriers. Lewy body pathology (LBP) in ADAD mainly occurs as olfactory only or amygdala-predominant variants. LBP develops late in the disease course in ADAD. CSF α-synuclein RT-QuIC has low sensitivity for focal, low-burden LBP.


Asunto(s)
Enfermedad de Alzheimer , Cuerpos de Lewy , alfa-Sinucleína , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , alfa-Sinucleína/líquido cefalorraquídeo , alfa-Sinucleína/genética , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/líquido cefalorraquídeo , Péptidos beta-Amiloides/metabolismo , Encéfalo/patología , Progresión de la Enfermedad , Cuerpos de Lewy/patología , Mutación
14.
Alzheimers Dement ; 20(9): 6590-6605, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39031528

RESUMEN

INTRODUCTION: The apolipoprotein E gene (APOE) is an established central player in the pathogenesis of Alzheimer's disease (AD), with distinct apoE isoforms exerting diverse effects. apoE influences not only amyloid-beta and tau pathologies but also lipid and energy metabolism, neuroinflammation, cerebral vascular health, and sex-dependent disease manifestations. Furthermore, ancestral background may significantly impact the link between APOE and AD, underscoring the need for more inclusive research. METHODS: In 2023, the Alzheimer's Association convened multidisciplinary researchers at the "AAIC Advancements: APOE" conference to discuss various topics, including apoE isoforms and their roles in AD pathogenesis, progress in apoE-targeted therapeutic strategies, updates on disease models and interventions that modulate apoE expression and function. RESULTS: This manuscript presents highlights from the conference and provides an overview of opportunities for further research in the field. DISCUSSION: Understanding apoE's multifaceted roles in AD pathogenesis will help develop targeted interventions for AD and advance the field of AD precision medicine. HIGHLIGHTS: APOE is a central player in the pathogenesis of Alzheimer's disease. APOE exerts a numerous effects throughout the brain on amyloid-beta, tau, and other pathways. The AAIC Advancements: APOE conference encouraged discussions and collaborations on understanding the role of APOE.


Asunto(s)
Enfermedad de Alzheimer , Apolipoproteínas E , Humanos , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Congresos como Asunto , Animales , Péptidos beta-Amiloides/metabolismo , Demencia/genética , Demencia/metabolismo , Investigación Biomédica
15.
Acta Neuropathol ; 145(6): 749-772, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37115208

RESUMEN

TREM2 is an innate immune receptor expressed by microglia in the adult brain. Genetic variation in the TREM2 gene has been implicated in risk for Alzheimer's disease and frontotemporal dementia, while homozygous TREM2 mutations cause a rare leukodystrophy, Nasu-Hakola disease (NHD). Despite extensive investigation, the role of TREM2 in NHD pathogenesis remains poorly understood. Here, we investigate the mechanisms by which a homozygous stop-gain TREM2 mutation (p.Q33X) contributes to NHD. Induced pluripotent stem cell (iPSC)-derived microglia (iMGLs) were generated from two NHD families: three homozygous TREM2 p.Q33X mutation carriers (termed NHD), two heterozygous mutation carriers, one related non-carrier, and two unrelated non-carriers. Transcriptomic and biochemical analyses revealed that iMGLs from NHD patients exhibited lysosomal dysfunction, downregulation of cholesterol genes, and reduced lipid droplets compared to controls. Also, NHD iMGLs displayed defective activation and HLA antigen presentation. This defective activation and lipid droplet content were restored by enhancing lysosomal biogenesis through mTOR-dependent and independent pathways. Alteration in lysosomal gene expression, such as decreased expression of genes implicated in lysosomal acidification (ATP6AP2) and chaperone mediated autophagy (LAMP2), together with reduction in lipid droplets were also observed in post-mortem brain tissues from NHD patients, thus closely recapitulating in vivo the phenotype observed in iMGLs in vitro. Our study provides the first cellular and molecular evidence that the TREM2 p.Q33X mutation in microglia leads to defects in lysosomal function and that compounds targeting lysosomal biogenesis restore a number of NHD microglial defects. A better understanding of how microglial lipid metabolism and lysosomal machinery are altered in NHD and how these defects impact microglia activation may provide new insights into mechanisms underlying NHD and other neurodegenerative diseases.


Asunto(s)
Enfermedad de Alzheimer , Microglía , Adulto , Humanos , Microglía/metabolismo , Metabolismo de los Lípidos/genética , Mutación con Pérdida de Función , Mutación/genética , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Lisosomas/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo , Receptor de Prorenina
16.
Alzheimers Dement ; 19(1): 79-96, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-35278341

RESUMEN

INTRODUCTION: Identifying CSF-based biomarkers for the ß-amyloidosis that initiates Alzheimer's disease (AD) could provide inexpensive and dynamic tests to distinguish AD from normal aging and predict future cognitive decline. METHODS: We developed immunoassays specifically detecting all C-terminal variants of secreted amyloid ß-protein and identified a novel biomarker, the Aß 37/42 ratio, that outperforms the canonical Aß42/40 ratio as a means to evaluate the γ-secretase activity and brain Aß accumulation. RESULTS: We show that Aß 37/42 can distinguish physiological and pathological status in (1) presenilin-1 mutant vs wild-type cultured cells, (2) AD vs control brain tissue, and (3) AD versus cognitively normal (CN) subjects in CSF, where 37/42 (AUC 0.9622) outperformed 42/40 (AUC 0.8651) in distinguishing CN from AD. DISCUSSION: We conclude that the Aß 37/42 ratio sensitively detects presenilin/γ-secretase dysfunction and better distinguishes CN from AD than Aß42/40 in CSF. Measuring this novel ratio alongside promising phospho-tau analytes may provide highly discriminatory fluid biomarkers for AD.


Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides , Secretasas de la Proteína Precursora del Amiloide , Proteínas tau , Fragmentos de Péptidos , Disfunción Cognitiva/diagnóstico , Biomarcadores
17.
Alzheimers Dement ; 19(5): 1785-1799, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36251323

RESUMEN

INTRODUCTION: The identification of multiple genetic risk factors for Alzheimer's disease (AD) suggests that many pathways contribute to AD onset and progression. However, the metabolomic and lipidomic profiles in carriers of distinct genetic risk factors are not fully understood. The metabolome can provide a direct image of dysregulated pathways in the brain. METHODS: We interrogated metabolomic signatures in the AD brain, including carriers of pathogenic variants in APP, PSEN1, and PSEN2 (autosomal dominant AD; ADAD), APOE ɛ4, and TREM2 risk variant carriers, and sporadic AD (sAD). RESULTS: We identified 133 unique and shared metabolites associated with ADAD, TREM2, and sAD. We identified a signature of 16 metabolites significantly altered between groups and associated with AD duration. DISCUSSION: AD genetic variants show distinct metabolic perturbations. Investigation of these metabolites may provide greater insight into the etiology of AD and its impact on clinical presentation. HIGHLIGHTS: APP/PSEN1/PSEN2 and TREM2 variant carriers show distinct metabolic changes. A total of 133 metabolites were differentially abundant in AD genetic groups. ß-citrylglutamate is differentially abundant in autosomal dominant, TREM2, and sporadic AD. A 16-metabolite profile shows differences between Alzheimer's disease (AD) genetic groups. The identified metabolic profile is associated with duration of disease.


Asunto(s)
Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Precursor de Proteína beta-Amiloide/genética , Encéfalo/patología , Heterocigoto , Lipidómica , Mutación , Presenilina-1/genética
18.
Alzheimers Dement ; 19(2): 632-645, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-35609137

RESUMEN

INTRODUCTION: As knowledge about neurological examination findings in autosomal dominant Alzheimer disease (ADAD) is incomplete, we aimed to determine the frequency and significance of neurological examination findings in ADAD. METHODS: Frequencies of neurological examination findings were compared between symptomatic mutation carriers and non mutation carriers from the Dominantly Inherited Alzheimer Network (DIAN) to define AD neurological examination findings. AD neurological examination findings were analyzed regarding frequency, association with and predictive value regarding cognitive decline, and association with brain atrophy in symptomatic mutation carriers. RESULTS: AD neurological examination findings included abnormal deep tendon reflexes, gait disturbance, pathological cranial nerve examination findings, tremor, abnormal finger to nose and heel to shin testing, and compromised motor strength. The frequency of AD neurological examination findings was 65.1%. Cross-sectionally, mutation carriers with AD neurological examination findings showed a more than two-fold faster cognitive decline and had greater parieto-temporal atrophy, including hippocampal atrophy. Longitudinally, AD neurological examination findings predicted a significantly greater decline over time. DISCUSSION: ADAD features a distinct pattern of neurological examination findings that is useful to estimate prognosis and may inform clinical care and therapeutic trial designs.


Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/patología , Disfunción Cognitiva/genética , Examen Neurológico
19.
Alzheimers Dement ; 19(1): 274-284, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-35362200

RESUMEN

INTRODUCTION: As the number of biomarkers used to study Alzheimer's disease (AD) continues to increase, it is important to understand the utility of any given biomarker, as well as what additional information a biomarker provides when compared to others. METHODS: We used hierarchical clustering to group 19 cross-sectional biomarkers in autosomal dominant AD. Feature selection identified biomarkers that were the strongest predictors of mutation status and estimated years from symptom onset (EYO). Biomarkers identified included clinical assessments, neuroimaging, cerebrospinal fluid amyloid, and tau, and emerging biomarkers of neuronal integrity and inflammation. RESULTS: Three primary clusters were identified: neurodegeneration, amyloid/tau, and emerging biomarkers. Feature selection identified amyloid and tau measures as the primary predictors of mutation status and EYO. Emerging biomarkers of neuronal integrity and inflammation were relatively weak predictors. DISCUSSION: These results provide novel insight into our understanding of the relationships among biomarkers and the staging of biomarkers based on disease progression.


Asunto(s)
Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides/líquido cefalorraquídeo , Proteínas Amiloidogénicas , Biomarcadores/líquido cefalorraquídeo , Estudios Transversales , Inflamación , Proteínas tau/genética , Proteínas tau/líquido cefalorraquídeo
20.
Neurobiol Dis ; 165: 105630, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35041990

RESUMEN

Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor expressed by macrophages and microglia in the central nervous system (CNS). TREM2 has attracted a lot of interest in the past decade for its critical role in modulating microglia functions under homeostatic conditions and in neurodegenerative diseases. Genetic variation in TREM2 is sufficient to cause Nasu-Hakola disease, a rare pre-senile dementia with bone cysts, and to increase risk for Alzheimer's disease, frontotemporal dementia, and other neurodegenerative disorders. Beyond the role played by TREM2 genetic variants in these diseases, TREM2 engagement is a key step in microglia activation in response to different types of tissue injury (e.g. ß-Amyloid deposition, demyelination, apoptotic cell death) leading to enhanced microglia metabolism, phagocytosis, proliferation and survival. TREM2 also exists as a soluble form (sTREM2), generated from receptor shedding or alternative splicing, which is detectable in plasma and cerebrospinal fluid (CSF). Genetic variation, physiological conditions and disease status impact CSF sTREM2 levels. Clinical and preclinical studies suggest that targeting and/or monitoring sTREM2 could have clinical and therapeutic implications. Despite the critical role of sTREM2 in neurologic disease, its function remains poorly understood. Here, we review the current literature on sTREM2 regarding its origin, genetic variation, and possible functions as a biomarker in neurological disorders and as a potential active player in CNS diseases and target for therapies.


Asunto(s)
Enfermedad de Alzheimer , Demencia Frontotemporal , Enfermedad de Alzheimer/metabolismo , Biomarcadores/metabolismo , Demencia Frontotemporal/genética , Humanos , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Microglía/metabolismo , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo
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