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1.
Biol Res ; 57(1): 46, 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-39014514

RESUMO

BACKGROUND: The nucleus incertus (NI) was originally described by Streeter in 1903, as a midline region in the floor of the fourth ventricle of the human brain with an 'unknown' function. More than a century later, the neuroanatomy of the NI has been described in lower vertebrates, but not in humans. Therefore, we examined the neurochemical anatomy of the human NI using markers, including the neuropeptide, relaxin-3 (RLN3), and began to explore the distribution of the NI-related RLN3 innervation of the hippocampus. METHODS: Histochemical staining of serial, coronal sections of control human postmortem pons was conducted to reveal the presence of the NI by detection of immunoreactivity (IR) for the neuronal markers, microtubule-associated protein-2 (MAP2), glutamic acid dehydrogenase (GAD)-65/67 and corticotrophin-releasing hormone receptor 1 (CRHR1), and RLN3, which is highly expressed in NI neurons in diverse species. RLN3 and vesicular GABA transporter 1 (vGAT1) mRNA were detected by fluorescent in situ hybridization. Pons sections containing the NI from an AD case were immunostained for phosphorylated-tau, to explore potential relevance to neurodegenerative diseases. Lastly, sections of the human hippocampus were stained to detect RLN3-IR and somatostatin (SST)-IR. RESULTS: In the dorsal, anterior-medial region of the human pons, neurons containing RLN3- and MAP2-IR, and RLN3/vGAT1 mRNA-positive neurons were observed in an anatomical pattern consistent with that of the NI in other species. GAD65/67- and CRHR1-immunopositive neurons were also detected within this area. Furthermore, RLN3- and AT8-IR were co-localized within NI neurons of an AD subject. Lastly, RLN3-IR was detected in neurons within the CA1, CA2, CA3 and DG areas of the hippocampus, in the absence of RLN3 mRNA. In the DG, RLN3- and SST-IR were co-localized in a small population of neurons. CONCLUSIONS: Aspects of the anatomy of the human NI are shared across species, including a population of stress-responsive, RLN3-expressing neurons and a RLN3 innervation of the hippocampus. Accumulation of phosphorylated-tau in the NI suggests its possible involvement in AD pathology. Further characterization of the neurochemistry of the human NI will increase our understanding of its functional role in health and disease.


Assuntos
Ponte , Humanos , Ponte/metabolismo , Masculino , Hipocampo/química , Hipocampo/metabolismo , Feminino , Relaxina/metabolismo , Relaxina/genética , Idoso , Neurônios/química , Memória/fisiologia , Proteínas Associadas aos Microtúbulos/metabolismo , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Glutamato Descarboxilase/metabolismo , Glutamato Descarboxilase/genética , Receptores de Hormônio Liberador da Corticotropina
2.
Alzheimers Dement ; 19(5): 1938-1946, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36373344

RESUMO

INTRODUCTION: The Alzheimer's Prevention Initiative Autosomal-Dominant Alzheimer's Disease (API ADAD) Trial evaluated the anti-oligomeric amyloid beta (Aß) antibody therapy crenezumab in cognitively unimpaired members of the Colombian presenilin 1 (PSEN1) E280A kindred. We report availability, methods employed to protect confidentiality and anonymity of participants, and process for requesting and accessing baseline data. METHODS: We developed mechanisms to share baseline data from the API ADAD Trial in consultation with experts and other groups sharing data from Alzheimer's disease (AD) prevention trials, balancing the need to protect anonymity and trial integrity with making data broadly available to accelerate progress in the field. We pressure-tested deliberate and inadvertent potential threats under specific assumptions, employed a system to suppress or mask both direct and indirect identifying variables, limited and firewalled data managers, and put forth specific principles requisite to receive data. RESULTS: Baseline demographic, PSEN1 E280A and apolipoprotein E genotypes, florbetapir and fluorodeoxyglucose positron emission tomography, magnetic resonance imaging, clinical, and cognitive data can now be requested by interested researchers. DISCUSSION: Baseline data are publicly available; treatment data and biological samples, including baseline and treatment-related blood-based biomarker data will become available in accordance with our original trial agreement and subsequently developed Collaboration for Alzheimer's Prevention principles. Sharing of these data will allow exploration of important questions including the differential effects of initiating an investigational AD prevention therapy both before as well as after measurable Aß plaque deposition.


Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/genética , Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides , Tomografia por Emissão de Pósitrons
3.
N Engl J Med ; 380(18): 1716-1725, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-30969506

RESUMO

BACKGROUND: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that has been associated with a history of repetitive head impacts. The neuropathological diagnosis is based on a specific pattern of tau deposition with minimal amyloid-beta deposition that differs from other disorders, including Alzheimer's disease. The feasibility of detecting tau and amyloid deposition in the brains of living persons at risk for CTE has not been well studied. METHODS: We used flortaucipir positron-emission tomography (PET) and florbetapir PET to measure deposition of tau and amyloid-beta, respectively, in the brains of former National Football League (NFL) players with cognitive and neuropsychiatric symptoms and in asymptomatic men with no history of traumatic brain injury. Automated image-analysis algorithms were used to compare the regional tau standardized uptake value ratio (SUVR, the ratio of radioactivity in a cerebral region to that in the cerebellum as a reference) between the two groups and to explore the associations of SUVR with symptom severity and with years of football play in the former-player group. RESULTS: A total of 26 former players and 31 controls were included in the analysis. The mean flortaucipir SUVR was higher among former players than among controls in three regions of the brain: bilateral superior frontal (1.09 vs. 0.98; adjusted mean difference, 0.13; 95% confidence interval [CI], 0.06 to 0.20; P<0.001), bilateral medial temporal (1.23 vs. 1.12; adjusted mean difference, 0.13; 95% CI, 0.05 to 0.21; P<0.001), and left parietal (1.12 vs. 1.01; adjusted mean difference, 0.12; 95% CI, 0.05 to 0.20; P = 0.002). In exploratory analyses, the correlation coefficients in these three regions between the SUVRs and years of play were 0.58 (95% CI, 0.25 to 0.79), 0.45 (95% CI, 0.07 to 0.71), and 0.50 (95% CI, 0.14 to 0.74), respectively. There was no association between tau deposition and scores on cognitive and neuropsychiatric tests. Only one former player had levels of amyloid-beta deposition similar to those in persons with Alzheimer's disease. CONCLUSIONS: A group of living former NFL players with cognitive and neuropsychiatric symptoms had higher tau levels measured by PET than controls in brain regions that are affected by CTE and did not have elevated amyloid-beta levels. Further studies are needed to determine whether elevated CTE-associated tau can be detected in individual persons. (Funded by Avid Radiopharmaceuticals and others.).


Assuntos
Encéfalo/patologia , Encefalopatia Traumática Crônica/patologia , Futebol Americano/lesões , Tomografia por Emissão de Pósitrons , Tauopatias/patologia , Proteínas tau/análise , Adulto , Idoso , Compostos de Anilina , Encéfalo/diagnóstico por imagem , Química Encefálica , Concussão Encefálica/complicações , Estudos de Casos e Controles , Encefalopatia Traumática Crônica/diagnóstico por imagem , Encefalopatia Traumática Crônica/etiologia , Transtornos Cognitivos/etiologia , Etilenoglicóis , Humanos , Masculino , Transtornos Mentais/etiologia , Pessoa de Meia-Idade , Placa Amiloide/diagnóstico por imagem , Compostos Radiofarmacêuticos , Tauopatias/diagnóstico por imagem
4.
Int J Mol Sci ; 23(24)2022 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-36555213

RESUMO

A reoccurring issue in neuroepigenomic studies, especially in the context of neurodegenerative disease, is the use of (heterogeneous) bulk tissue, which generates noise during epigenetic profiling. A workable solution to this issue is to quantify epigenetic patterns in individually isolated neuronal cells using laser capture microdissection (LCM). For this purpose, we established a novel approach for targeted DNA methylation profiling of individual genes that relies on a combination of LCM and limiting dilution bisulfite pyrosequencing (LDBSP). Using this approach, we determined cytosine-phosphate-guanine (CpG) methylation rates of single alleles derived from 50 neurons that were isolated from unfixed post-mortem brain tissue. In the present manuscript, we describe the general workflow and, as a showcase, demonstrate how targeted methylation analysis of various genes, in this case, RHBDF2, OXT, TNXB, DNAJB13, PGLYRP1, C3, and LMX1B, can be performed simultaneously. By doing so, we describe an adapted data analysis pipeline for LDBSP, allowing one to include and correct CpG methylation rates derived from multi-allele reactions. In addition, we show that the efficiency of LDBSP on DNA derived from LCM neurons is similar to the efficiency obtained in previously published studies using this technique on other cell types. Overall, the method described here provides the user with a more accurate estimation of the DNA methylation status of each target gene in the analyzed cell pools, thereby adding further validity to this approach.


Assuntos
Doenças Neurodegenerativas , Humanos , Análise de Sequência de DNA/métodos , Metilação de DNA , Encéfalo , Sequenciamento de Nucleotídeos em Larga Escala , Lasers , Chaperonas Moleculares , Proteínas Reguladoras de Apoptose
5.
Mol Syst Biol ; 16(12): e9819, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33289969

RESUMO

Alzheimer's disease (AD) is characterized by the appearance of amyloid-ß plaques, neurofibrillary tangles, and inflammation in brain regions involved in memory. Using mass spectrometry, we have quantified the phosphoproteome of the CK-p25, 5XFAD, and Tau P301S mouse models of neurodegeneration. We identified a shared response involving Siglec-F which was upregulated on a subset of reactive microglia. The human paralog Siglec-8 was also upregulated on microglia in AD. Siglec-F and Siglec-8 were upregulated following microglial activation with interferon gamma (IFNγ) in BV-2 cell line and human stem cell-derived microglia models. Siglec-F overexpression activates an endocytic and pyroptotic inflammatory response in BV-2 cells, dependent on its sialic acid substrates and immunoreceptor tyrosine-based inhibition motif (ITIM) phosphorylation sites. Related human Siglecs induced a similar response in BV-2 cells. Collectively, our results point to an important role for mouse Siglec-F and human Siglec-8 in regulating microglial activation during neurodegeneration.


Assuntos
Inflamação/patologia , Microglia/metabolismo , Degeneração Neural/patologia , Fosfoproteínas/metabolismo , Proteômica , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Sequência de Aminoácidos , Animais , Anticorpos/metabolismo , Morte Celular , Linhagem Celular , Humanos , Inflamação/metabolismo , Interferon gama/metabolismo , Camundongos Transgênicos , Microglia/patologia , Degeneração Neural/metabolismo , Peptídeos/metabolismo , Fagocitose , Fosfotirosina/metabolismo , Proteoma/metabolismo , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/química , Transdução de Sinais , Regulação para Cima
6.
Acta Neuropathol ; 140(3): 295-315, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32666270

RESUMO

MicroRNAs are recognized as important regulators of many facets of physiological brain function while also being implicated in the pathogenesis of several neurological disorders. Dysregulation of miR155 is widely reported across a variety of neurodegenerative conditions, including Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, and traumatic brain injury. In previous work, we observed that experimentally validated miR155 gene targets were consistently enriched among genes identified as differentially expressed across multiple brain tissue and disease contexts. In particular, we found that human herpesvirus-6A (HHV-6A) suppressed miR155, recapitulating reports of miR155 inhibition by HHV-6A in infected T-cells, thyrocytes, and natural killer cells. In earlier studies, we also reported the effects of constitutive deletion of miR155 on accelerating the accumulation of Aß deposits in 4-month-old APP/PSEN1 mice. Herein, we complete the cumulative characterization of transcriptomic, electrophysiological, neuropathological, and learning behavior profiles from 4-, 8- and 10-month-old WT and APP/PSEN1 mice in the absence or presence of miR155. We also integrated human post-mortem brain RNA-sequences from four independent AD consortium studies, together comprising 928 samples collected from six brain regions. We report that gene expression perturbations associated with miR155 deletion in mouse cortex are in aggregate observed to be concordant with AD-associated changes across these independent human late-onset AD (LOAD) data sets, supporting the relevance of our findings to human disease. LOAD has recently been formulated as the clinicopathological manifestation of a multiplex of genetic underpinnings and pathophysiological mechanisms. Our accumulated data are consistent with such a formulation, indicating that miR155 may be uniquely positioned at the intersection of at least four components of this LOAD "multiplex": (1) innate immune response pathways; (2) viral response gene networks; (3) synaptic pathology; and (4) proamyloidogenic pathways involving the amyloid ß peptide (Aß).


Assuntos
Doença de Alzheimer/genética , Encéfalo/patologia , MicroRNAs/genética , Transcriptoma/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Redes Reguladoras de Genes/genética , Humanos , Camundongos Transgênicos , Doenças do Sistema Nervoso/patologia , Placa Amiloide/patologia
7.
Alzheimers Dement ; 14(11): 1438-1449, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29792870

RESUMO

INTRODUCTION: Genome-wide association studies consistently show that single nucleotide polymorphisms (SNPs) in the complement receptor 1 (CR1) gene modestly but significantly alter Alzheimer's disease (AD) risk. Follow-up research has assumed that CR1 is expressed in the human brain despite a paucity of evidence for its function there. Alternatively, erythrocytes contain >80% of the body's CR1, where, in primates, it is known to bind circulating pathogens. METHODS: Multidisciplinary methods were employed. RESULTS: Conventional Western blots and quantitative polymerase chain reaction failed to detect CR1 in the human brain. Brain immunohistochemistry revealed only vascular CR1. By contrast, erythrocyte CR1 immunoreactivity was readily observed and was significantly deficient in AD, as was CR1-mediated erythrocyte capture of circulating amyloid ß peptide. CR1 SNPs associated with decreased erythrocyte CR1 increased AD risk, whereas a CR1 SNP associated with increased erythrocyte CR1 decreased AD risk. DISCUSSION: SNP effects on erythrocyte CR1 likely underlie the association of CR1 polymorphisms with AD risk.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Polimorfismo de Nucleotídeo Único , Receptores de Complemento 3b/genética , Receptores de Complemento 3b/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Apolipoproteínas E/genética , Eritrócitos/metabolismo , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Microglia/metabolismo , Neocórtex/metabolismo , Estudos Prospectivos , Isoformas de Proteínas , Receptores de Complemento 3b/química
8.
Alzheimers Dement ; 14(6): 775-786, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29396107

RESUMO

INTRODUCTION: Our laboratories have demonstrated that accumulation of oligomeric amyloid ß (OAß) in neurons is an essential step leading to OAß-mediated mitochondrial dysfunction. METHODS: Alzheimer's disease (AD) and matching control hippocampal neurons, astrocytes, and microglia were isolated by laser-captured microdissection from the same subjects, followed by whole-transcriptome sequencing. Complementary in vitro work was performed in OAß-treated differentiated SH-SY5Y, followed by the use of a novel CoQ10 analogue for protection. This compound is believed to be effective both in suppressing reactive oxygen species and also functioning in mitochondrial electron transport. RESULTS: We report decreases in the same mitochondrial-encoded mRNAs in Alzheimer's disease laser-captured CA1 neurons and in OAß-treated SH-SY5Y cells, but not in laser-captured microglia and astrocytes. Pretreatment with a novel CoQ10 analogue, protects neuronal mitochondria from OAß-induced mitochondrial changes. DISCUSSION: Similarity of expression changes in neurons from Alzheimer's disease brain and neuronal cells treated with OAß, and the effect of a CoQ10 analogue on the latter, suggests a pretreatment option to prevent OAß toxicity, long before the damage is apparent.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Neurônios/metabolismo , RNA Mensageiro/metabolismo , RNA Mitocondrial/metabolismo , Idoso , Doença de Alzheimer/metabolismo , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Linhagem Celular Tumoral , Feminino , Hipocampo/metabolismo , Humanos , Técnicas In Vitro , Microdissecção e Captura a Laser , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microscopia Eletrônica de Transmissão , Neurônios/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mitocondrial/genética , Ubiquinona/análogos & derivados , Ubiquinona/farmacologia
9.
Alzheimers Dement ; 13(5): 510-519, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-27793643

RESUMO

INTRODUCTION: We have comprehensively described the expression profiles of mitochondrial DNA and nuclear DNA genes that encode subunits of the respiratory oxidative phosphorylation (OXPHOS) complexes (I-V) in the hippocampus from young controls, age matched, mild cognitively impaired (MCI), and Alzheimer's disease (AD) subjects. METHODS: Hippocampal tissues from 44 non-AD controls (NC), 10 amnestic MCI, and 18 AD cases were analyzed on Affymetrix Hg-U133 plus 2.0 arrays. RESULTS: The microarray data revealed significant down regulation in OXPHOS genes in AD, particularly those encoded in the nucleus. In contrast, there was up regulation of the same gene(s) in MCI subjects compared to AD and ND cases. No significant differences were observed in mtDNA genes identified in the array between AD, ND, and MCI subjects except one mt-ND6. DISCUSSION: Our findings suggest that restoration of the expression of nuclear-encoded OXPHOS genes in aging could be a viable strategy for blunting AD progression.


Assuntos
Envelhecimento/genética , Doença de Alzheimer/genética , Transtornos Cognitivos/genética , Mitocôndrias/genética , Fosforilação Oxidativa , Adulto , Idoso de 80 Anos ou mais , Autopsia , Feminino , Hipocampo , Humanos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos
10.
Alzheimers Dement ; 13(12): 1397-1409, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28475854

RESUMO

INTRODUCTION: Although amyloid ß peptide (Aß) is cleared from the brain to cerebrospinal fluid and the peripheral circulation, mechanisms for its removal from blood remain unresolved. Primates have uniquely evolved a highly effective peripheral clearance mechanism for pathogens, immune adherence, in which erythrocyte complement receptor 1 (CR1) plays a major role. METHODS: Multidisciplinary methods were used to demonstrate immune adherence capture of Aß by erythrocytes and its deficiency in Alzheimer's disease (AD). RESULTS: Aß was shown to be subject to immune adherence at every step in the pathway. Aß dose-dependently activated serum complement. Complement-opsonized Aß was captured by erythrocytes via CR1. Erythrocytes, Aß, and hepatic Kupffer cells were colocalized in the human liver. Significant deficits in erythrocyte Aß levels were found in AD and mild cognitive impairment patients. DISCUSSION: CR1 polymorphisms elevate AD risk, and >80% of human CR1 is vested in erythrocytes to subserve immune adherence. The present results suggest that this pathway is pathophysiologically relevant in AD.


Assuntos
Doença de Alzheimer/sangue , Peptídeos beta-Amiloides/metabolismo , Disfunção Cognitiva/sangue , Eritrócitos/metabolismo , Fragmentos de Peptídeos/metabolismo , Receptores de Complemento/fisiologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/farmacologia , Animais , Estudos de Casos e Controles , Disfunção Cognitiva/patologia , Disfunção Cognitiva/fisiopatologia , Relação Dose-Resposta a Droga , Eritrócitos/efeitos dos fármacos , Feminino , Humanos , Fígado/metabolismo , Fígado/patologia , Fígado/ultraestrutura , Macaca fascicularis/sangue , Masculino , Testes de Estado Mental e Demência , Microscopia Eletrônica , Pessoa de Meia-Idade , Fragmentos de Peptídeos/farmacologia , Ligação Proteica/efeitos dos fármacos , Receptores de Complemento/genética
11.
Neurobiol Aging ; 141: 160-170, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38964013

RESUMO

Women have a higher incidence of Alzheimer's disease (AD), even after adjusting for increased longevity. Thus, there is an urgent need to identify genes that underpin sex-associated risk of AD. PIN1 is a key regulator of the tau phosphorylation signaling pathway; however, potential differences in PIN1 expression, in males and females, are still unknown. We analyzed brain transcriptomic datasets focusing on sex differences in PIN1 mRNA levels in an aging and AD cohort, which revealed reduced PIN1 levels primarily within females. We validated this observation in an independent dataset (ROS/MAP), which also revealed that PIN1 is negatively correlated with multiregional neurofibrillary tangle density and global cognitive function in females only. Additional analysis revealed a decrease in PIN1 in subjects with mild cognitive impairment (MCI) compared with aged individuals, again driven predominantly by female subjects. Histochemical analysis of PIN1 in AD and control male and female neocortex revealed an overall decrease in axonal PIN1 protein levels in females. These findings emphasize the importance of considering sex differences in AD research.


Assuntos
Doença de Alzheimer , Cognição , Disfunção Cognitiva , Peptidilprolil Isomerase de Interação com NIMA , Neocórtex , Emaranhados Neurofibrilares , Caracteres Sexuais , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Doença de Alzheimer/metabolismo , Peptidilprolil Isomerase de Interação com NIMA/genética , Peptidilprolil Isomerase de Interação com NIMA/metabolismo , Humanos , Feminino , Neocórtex/patologia , Neocórtex/metabolismo , Masculino , Disfunção Cognitiva/genética , Disfunção Cognitiva/patologia , Disfunção Cognitiva/metabolismo , Idoso , Idoso de 80 Anos ou mais , Emaranhados Neurofibrilares/patologia , Emaranhados Neurofibrilares/metabolismo , Fenótipo , Sistema Límbico/patologia , Sistema Límbico/metabolismo , Expressão Gênica , Envelhecimento/patologia , Envelhecimento/genética , Envelhecimento/metabolismo , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Proteínas tau/metabolismo , Proteínas tau/genética , Fosforilação
12.
Nat Commun ; 15(1): 5815, 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38987616

RESUMO

The emergence of single nucleus RNA sequencing (snRNA-seq) offers to revolutionize the study of Alzheimer's disease (AD). Integration with complementary multiomics data such as genetics, proteomics and clinical data provides powerful opportunities to link cell subpopulations and molecular networks with a broader disease-relevant context. We report snRNA-seq profiles from superior frontal gyrus samples from 101 well characterized subjects from the Banner Brain and Body Donation Program in combination with whole genome sequences. We report findings that link common AD risk variants with CR1 expression in oligodendrocytes as well as alterations in hematological parameters. We observed an AD-associated CD83(+) microglial subtype with unique molecular networks and which is associated with immunoglobulin IgG4 production in the transverse colon. Our major observations were replicated in two additional, independent snRNA-seq data sets. These findings illustrate the power of multi-tissue molecular profiling to contextualize snRNA-seq brain transcriptomics and reveal disease biology.


Assuntos
Doença de Alzheimer , Análise de Célula Única , Transcriptoma , Humanos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Masculino , Feminino , Idoso , Microglia/metabolismo , Idoso de 80 Anos ou mais , Oligodendroglia/metabolismo , Pessoa de Meia-Idade , Imunoglobulina G/metabolismo , Redes Reguladoras de Genes , Análise de Sequência de RNA , Encéfalo/metabolismo , Encéfalo/patologia , Perfilação da Expressão Gênica
13.
bioRxiv ; 2023 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-37645898

RESUMO

Women have a higher incidence of Alzheimer's disease (AD), even after adjusting for increased longevity. Thus, there is an urgent need to identify the molecular networks that underpin the sex-associated risk of AD. Recent efforts have identified PIN1 as a key regulator of tau phosphorylation signaling pathway. Pin1 is the only gene, to date, that when deleted can cause both tau and Aß-related pathologies in an age-dependent manner. We analyzed multiple brain transcriptomic datasets focusing on sex differences in PIN1 mRNA levels, in an aging and AD cohort, which revealed reduced PIN1 levels driven by females. Then, we validated this observation in an independent dataset (ROS/MAP) which also revealed that PIN1 is negatively correlated with multiregional neurofibrillary tangle density and global cognitive function, in females only. Additional analysis revealed a decrease in PIN1 in subjects with mild cognitive impairment (MCI) compared with aged individuals, again, driven predominantly by female subjects. Our results show that while both male and female AD patients show decreased PIN1 expression, changes occur before the onset of clinical symptoms of AD in females and correlate to early events associated with AD risk (e.g., synaptic dysfunction). These changes are specific to neurons, and may be a potential prognostic marker to assess AD risk in the aging population and even more so in AD females with increased risk of AD.

14.
bioRxiv ; 2023 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-37961404

RESUMO

The emergence of technologies that can support high-throughput profiling of single cell transcriptomes offers to revolutionize the study of brain tissue from persons with and without Alzheimer's disease (AD). Integration of these data with additional complementary multiomics data such as genetics, proteomics and clinical data provides powerful opportunities to link observed cell subpopulations and molecular network features within a broader disease-relevant context. We report here single nucleus RNA sequencing (snRNA-seq) profiles generated from superior frontal gyrus cortical tissue samples from 101 exceptionally well characterized, aged subjects from the Banner Brain and Body Donation Program in combination with whole genome sequences. We report findings that link common AD risk variants with CR1 expression in oligodendrocytes as well as alterations in peripheral hematological lab parameters, with these observations replicated in an independent, prospective cohort study of ageing and dementia. We also observed an AD-associated CD83(+) microglial subtype with unique molecular networks that encompass many known regulators of AD-relevant microglial biology, and which are associated with immunoglobulin IgG4 production in the transverse colon. These findings illustrate the power of multi-tissue molecular profiling to contextualize snRNA-seq brain transcriptomics and reveal novel disease biology. The transcriptomic, genetic, phenotypic, and network data resources described within this study are available for access and utilization by the scientific community.

15.
Sci Rep ; 13(1): 10405, 2023 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-37369829

RESUMO

Mitochondrial (MT) dysfunction has been associated with several neurodegenerative diseases including Alzheimer's disease (AD). While MT-copy number differences have been implicated in AD, the effect of MT heteroplasmy on AD has not been well characterized. Here, we analyzed over 1800 whole genome sequencing data from four AD cohorts in seven different tissue types to determine the extent of MT heteroplasmy present. While MT heteroplasmy was present throughout the entire MT genome for blood samples, we detected MT heteroplasmy only within the MT control region for brain samples. We observed that an MT variant 10398A>G (rs2853826) was significantly associated with overall MT heteroplasmy in brain tissue while also being linked with the largest number of distinct disease phenotypes of all annotated MT variants in MitoMap. Using gene-expression data from our brain samples, our modeling discovered several gene networks involved in mitochondrial respiratory chain and Complex I function associated with 10398A>G. The variant was also found to be an expression quantitative trait loci (eQTL) for the gene MT-ND3. We further characterized the effect of 10398A>G by phenotyping a population of lymphoblastoid cell-lines (LCLs) with and without the variant allele. Examination of RNA sequence data from these LCLs reveal that 10398A>G was an eQTL for MT-ND4. We also observed in LCLs that 10398A>G was significantly associated with overall MT heteroplasmy within the MT control region, confirming the initial findings observed in post-mortem brain tissue. These results provide novel evidence linking MT SNPs with MT heteroplasmy and open novel avenues for the investigation of pathomechanisms that are driven by this pleiotropic disease associated loci.


Assuntos
Heteroplasmia , Mitocôndrias , Mitocôndrias/genética , Polimorfismo de Nucleotídeo Único , Fenótipo , Sequência de Bases , DNA Mitocondrial/genética
16.
J Neurotrauma ; 39(19-20): 1429-1441, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35593008

RESUMO

Severe traumatic brain injury (TBI) results in cognitive dysfunction in part due to vascular perturbations. In contrast, the long-term vasculo-cognitive pathophysiology of mild TBI (mTBI) remains unknown. We evaluated mTBI effects on chronic cognitive and cerebrovascular function and assessed their interrelationships. Sprague-Dawley rats received midline fluid percussion injury (n = 20) or sham (n = 21). Cognitive function was assessed (3- and 6-month novel object recognition [NOR], novel object location [NOL], and temporal order object recognition [TOR]). Six-month cerebral blood flow (CBF) and cerebral blood volume (CBV) using contrast magnetic resonance imaging (MRI) and ex vivo circle of Willis artery endothelial and smooth muscle-dependent function were measured. mTBI rats showed significantly impaired NOR, with similar trends (non-significant) in NOL/TOR. Regional CBF and CBV were similar in sham and mTBI. NOR correlated with CBF in lateral hippocampus, medial hippocampus, and primary somatosensory barrel cortex, whereas it inversely correlated with arterial smooth muscle-dependent dilation. Six-month baseline endothelial and smooth muscle-dependent arterial function were similar among mTBI and sham, but post-angiotensin 2 stimulation, mTBI showed no change in smooth muscle-dependent dilation from baseline response, unlike the reduction in sham. mTBI led to chronic cognitive dysfunction and altered angiotensin 2-stimulated smooth muscle-dependent vasoreactivity. The findings of persistent pathophysiological consequences of mTBI in this animal model add to the broader understanding of chronic pathophysiological sequelae in human mild TBI.


Assuntos
Concussão Encefálica , Circulação Cerebrovascular , Cognição , Animais , Humanos , Ratos , Angiotensinas , Concussão Encefálica/complicações , Concussão Encefálica/patologia , Ratos Sprague-Dawley
17.
Neuron ; 54(5): 713-20, 2007 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-17553421

RESUMO

The apolipoprotein E (APOE) epsilon4 allele is the best established genetic risk factor for late-onset Alzheimer's disease (LOAD). We conducted genome-wide surveys of 502,627 single-nucleotide polymorphisms (SNPs) to characterize and confirm other LOAD susceptibility genes. In epsilon4 carriers from neuropathologically verified discovery, neuropathologically verified replication, and clinically characterized replication cohorts of 1411 cases and controls, LOAD was associated with six SNPs from the GRB-associated binding protein 2 (GAB2) gene and a common haplotype encompassing the entire GAB2 gene. SNP rs2373115 (p = 9 x 10(-11)) was associated with an odds ratio of 4.06 (confidence interval 2.81-14.69), which interacts with APOE epsilon4 to further modify risk. GAB2 was overexpressed in pathologically vulnerable neurons; the Gab2 protein was detected in neurons, tangle-bearing neurons, and dystrophic neuritis; and interference with GAB2 gene expression increased tau phosphorylation. Our findings suggest that GAB2 modifies LOAD risk in APOE epsilon4 carriers and influences Alzheimer's neuropathology.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Apolipoproteína E4/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Química Encefálica/genética , Linhagem Celular Tumoral , Análise Mutacional de DNA , Regulação da Expressão Gênica/genética , Frequência do Gene , Marcadores Genéticos/genética , Testes Genéticos , Haplótipos/genética , Humanos , Mutação , Emaranhados Neurofibrilares/genética , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Fosforilação , Fatores de Risco , Proteínas tau/metabolismo
18.
Proc Natl Acad Sci U S A ; 105(11): 4441-6, 2008 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-18332434

RESUMO

Alzheimer's disease (AD) is associated with regional reductions in fluorodeoxyglucose positron emission tomography (FDG PET) measurements of the cerebral metabolic rate for glucose, which may begin long before the onset of histopathological or clinical features, especially in carriers of a common AD susceptibility gene. Molecular evaluation of cells from metabolically affected brain regions could provide new information about the pathogenesis of AD and new targets at which to aim disease-slowing and prevention therapies. Data from a genome-wide transcriptomic study were used to compare the expression of 80 metabolically relevant nuclear genes from laser-capture microdissected non-tangle-bearing neurons from autopsy brains of AD cases and normal controls in posterior cingulate cortex, which is metabolically affected in the earliest stages; other brain regions metabolically affected in PET studies of AD or normal aging; and visual cortex, which is relatively spared. Compared with controls, AD cases had significantly lower expression of 70% of the nuclear genes encoding subunits of the mitochondrial electron transport chain in posterior cingulate cortex, 65% of those in the middle temporal gyrus, 61% of those in hippocampal CA1, 23% of those in entorhinal cortex, 16% of those in visual cortex, and 5% of those in the superior frontal gyrus. Western blots confirmed underexpression of those complex I-V subunits assessed at the protein level. Cerebral metabolic rate for glucose abnormalities in FDG PET studies of AD may be associated with reduced neuronal expression of nuclear genes encoding subunits of the mitochondrial electron transport chain.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Metabolismo Energético , Regulação da Expressão Gênica/genética , Neurônios/metabolismo , Idoso , Encéfalo/metabolismo , Feminino , Humanos , Masculino
19.
Nat Aging ; 1(6): 550-565, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-37117831

RESUMO

Alzheimer's disease (AD) is a form of dementia characterized by amyloid-ß plaques and tau neurofibrillary tangles that progressively disrupt neural circuits in the brain. The signaling networks underlying AD pathological changes are poorly characterized at the phosphoproteome level. Using mass spectrometry, we analyzed the proteome and tyrosine, serine and threonine phosphoproteomes of temporal cortex tissue from patients with AD and aged-matched controls. We identified cocorrelated peptide clusters that were linked to varying levels of phospho-tau, oligodendrocyte, astrocyte, microglia and neuron pathologies. We found that neuronal synaptic protein abundances were strongly anti-correlated with markers of microglial reactivity. We also observed that phosphorylation sites on kinases targeting tau and other new signaling factors were correlated with these peptide modules. Finally, we used data-driven statistical modeling to identify individual peptides and peptide clusters that were predictive of AD histopathologies. Together, these results build a map of pathology-associated phosphorylation signaling events occurring in AD.


Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/metabolismo , Proteínas tau/metabolismo , Emaranhados Neurofibrilares/metabolismo , Peptídeos beta-Amiloides/metabolismo , Neurônios/metabolismo , Placa Amiloide/metabolismo
20.
Neurobiol Aging ; 97: 56-64, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33157432

RESUMO

Pharmacological phosphodiesterase 4D (PDE4D) inhibition shows therapeutic potential to restore memory function in Alzheimer's disease (AD), but will likely evoke adverse side effects. As PDE4D encodes multiple isoforms, targeting specific isoforms may improve treatment efficacy and safety. Here, we investigated whether PDE4D isoform expression and PDE4D DNA methylation is affected in AD and whether expression changes are associated with severity of pathology and cognitive impairment. In post-mortem temporal lobe brain material from AD patients (n = 42) and age-matched controls (n = 40), we measured PDE4D isoform expression and PDE4D DNA (hydroxy)methylation using quantitative polymerase chain reaction and Illumina 450k Beadarrays, respectively. Linear regression revealed increased PDE4D1, -D3, -D5, and -D8 expression in AD with concurrent (hydroxy)methylation changes in associated promoter regions. Moreover, increased PDE4D1 and -D3 expression was associated with higherplaque and tau pathology levels, higher Braak stages, and progressed cognitive impairment. Future studies should indicate functional roles of specific PDE4D isoforms and the efficacy and safety of their selective inhibition to restore memory function in AD.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Expressão Gênica/genética , Estudos de Associação Genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/complicações , Disfunção Cognitiva/patologia , Estudos de Coortes , Feminino , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Masculino
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