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1.
Methods Mol Biol ; 2785: 165-175, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38427194

RESUMO

Amyloid plaques are a neuropathologic hallmark of Alzheimer's disease (AD), which can be imaged through positron emission tomography (PET) technology using radiopharmaceuticals that selectively bind to the fibrillar aggregates of amyloid-ß plaques (Amy-PET). Several radiotracers for amyloid PET have been validated (11C-Pittsburgh compound B and the 18F-labeled compounds such as 18F-florbetaben, 18F-florbetapir, and 18F-flutemetamol). Images can be interpreted by means of visual/qualitative, semiquantitative, and quantitative criteria. Here, we summarize the main differences between the available radiotracers for Amy-PET, the proposed interpretation criteria, and main proposed quantification methods.


Assuntos
Doença de Alzheimer , Tomografia por Emissão de Pósitrons , Humanos , Tomografia por Emissão de Pósitrons/métodos , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Amiloide/metabolismo , Compostos Radiofarmacêuticos/metabolismo , Compostos de Anilina/metabolismo , Placa Amiloide/metabolismo , Encéfalo/metabolismo
2.
Methods Mol Biol ; 2785: 271-285, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38427199

RESUMO

Alzheimer's disease is pathologically featured by the accumulation of amyloid-beta (Aß) plaque and neurofibrillary tangles. Compared to small animal positron emission tomography, optical imaging features nonionizing radiation, low cost, and logistic convenience. Optical detection of Aß deposits is typically implemented by 2D macroscopic imaging and various microscopic techniques assisted with Aß-targeted contrast agents. Here, we introduce fluorescence molecular tomography (FMT), a macroscopic 3D fluorescence imaging technique, convenient for in vivo longitudinal monitoring of the animal brain without the involvement of cranial window opening operation. This chapter aims to provide the protocols for FMT in vivo imaging of Aß deposits in the brain of rodent model of Alzheimer's disease. The materials, stepwise method, notes, limitations of FMT, and emerging opportunities for FMT techniques are presented.


Assuntos
Doença de Alzheimer , Amiloidose , Camundongos , Animais , Doença de Alzheimer/diagnóstico por imagem , Meios de Contraste , Fluorescência , Peptídeos beta-Amiloides/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Placa Amiloide/diagnóstico por imagem , Camundongos Transgênicos , Modelos Animais de Doenças
3.
Methods Mol Biol ; 2785: 195-218, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38427196

RESUMO

The recent progress in the development of in vivo biomarkers is rapidly changing how neurodegenerative diseases are conceptualized and diagnosed and how clinical trials are designed today. Alzheimer's disease (AD) - the most common neurodegenerative disorder - is characterized by a complex neuropathology involving the deposition of extracellular amyloid-ß (Aß) plaques and intracellular neurofibrillary tangles (NFTs) of hyperphosphorylated tau proteins, accompanied by the activation of glial cells, i.e., astrocytes and microglia, and neuroinflammatory response, leading to neurodegeneration and cognitive dysfunction. An increasing diversity of positron emission tomography (PET) imaging radiotracers is available to selectively target the different pathophysiological processes of AD. Along with the success of Aß PET and the more recent tau PET imaging, there is a great interest to develop PET tracers to image glial reactivity and neuroinflammation. While most research to date has focused on imaging microgliosis, there is an upsurge of interest in imaging reactive astrocytes in the AD continuum. There is increasing evidence that reactive astrocytes are morphologically and functionally heterogeneous, with different subtypes that express different markers and display various homeostatic or detrimental roles across disease stages. Therefore, multiple biomarkers are desirable to unravel the complex phenomenon of reactive astrocytosis. In the field of in vivo PET imaging in AD, the research concerning reactive astrocytes has predominantly focused on targeting monoamine oxidase B (MAO-B), most often using either 11C-deuterium-L-deprenyl (11C-DED) or 18F-SMBT-1 PET tracers. Additionally, imidazoline2 binding (I2BS) sites have been imaged using 11C-BU99008 PET. Recent studies in our group using 11C-DED PET imaging suggest that astrocytosis may be present from the early stages of disease development in AD. This chapter provides a detailed description of the practical approach used for the analysis of 11C-DED PET imaging data in a multitracer PET paradigm including 11C-Pittsburgh compound B (11C-PiB) and 18F-fluorodeoxyglucose (18F-FDG). The multitracer PET approach allows investigating the comparative regional and temporal patterns of in vivo brain astrocytosis, fibrillar Aß deposition, glucose metabolism, and brain structural changes. It may also contribute to understanding the potential role of novel plasma biomarkers of reactive astrocytes, in particular the glial fibrillary acidic protein (GFAP), at different stages of disease progression. This chapter attempts to stimulate further research in the field, including the development of novel PET tracers that may allow visualizing different aspects of the complex astrocytic and microglial response in neurodegenerative diseases. Progress in the field will contribute to the incorporation of PET imaging of glial reactivity and neuroinflammation as biomarkers with clinical application and motivate further investigation on glial cells as therapeutic targets in AD and other neurodegenerative diseases.


Assuntos
Doença de Alzheimer , Gliose , Humanos , Gliose/metabolismo , Doenças Neuroinflamatórias , Doença de Alzheimer/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Fluordesoxiglucose F18/metabolismo , Inflamação/metabolismo , Placa Amiloide/metabolismo , Biomarcadores/metabolismo
4.
Int J Mol Sci ; 25(5)2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38473822

RESUMO

Several genetic variants that affect microglia function have been identified as risk factors for Alzheimer's Disease (AD), supporting the importance of this cell type in disease progression. However, the effect of autosomal dominant mutations in the amyloid precursor protein (APP) or the presenilin (PSEN1/2) genes has not been addressed in microglia in vivo. We xenotransplanted human microglia derived from non-carriers and carriers of autosomal dominant AD (ADAD)-causing mutations in the brain of hCSF1 WT or 5XFAD mice. We observed that ADAD mutations in microglia are not sufficient to trigger amyloid pathology in WT mice. In 5XFAD mice, we observed a non-statistically significant increase in amyloid plaque volume and number of dystrophic neurites, coupled with a reduction in plaque-associated microglia in the brain of mice xenotransplanted with ADAD human microglia compared to mice xenotransplanted with non-ADAD microglia. In addition, we observed a non-statistically significant impairment in working and contextual memory in 5XFAD mice xenotransplanted with ADAD microglia compared to those xenotransplanted with non-ADAD-carrier microglia. We conclude that, although not sufficient to initiate amyloid pathology in the healthy brain, mutations in APP and PSEN1 in human microglia might cause mild changes in pathological and cognitive outcomes in 5XFAD mice in a manner consistent with increased AD risk.


Assuntos
Doença de Alzheimer , Humanos , Animais , Camundongos , Microglia , Proteínas Amiloidogênicas , Precursor de Proteína beta-Amiloide , Mutação , Placa Amiloide , Presenilina-1 , Peptídeos beta-Amiloides , Camundongos Transgênicos , Modelos Animais de Doenças
5.
J Am Coll Cardiol ; 83(11): 1085-1099, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38479957

RESUMO

Cardiac amyloidosis is increasingly recognized as a treatable form of heart failure. Highly effective specific therapies have recently become available for the 2 most frequent forms of cardiac amyloidosis: immunoglobulin light chain amyloidosis and transthyretin (ATTR) amyloidosis. Nevertheless, initiation of specific therapies requires recognition of cardiac amyloidosis and appropriate characterization of the amyloid type. Although noninvasive diagnosis is possible for ATTR cardiac amyloidosis, histological demonstration and typing of amyloid deposits is still required for a substantial number of patients with ATTR and in all patients with light chain amyloidosis and other rarer forms of cardiac amyloidosis. Amyloid histological typing can be performed using different techniques: mass spectrometry, immunohistochemistry, and immunoelectron microscopy. This review describes which patients require histological confirmation of cardiac amyloidosis along with when and how to type amyloid deposits in histologic specimens. Furthermore, it covers the characteristics and limitations of the different typing methods that are available in clinical practice.


Assuntos
Neuropatias Amiloides Familiares , Amiloidose , Cardiomiopatias , Insuficiência Cardíaca , Humanos , Placa Amiloide , Amiloidose/patologia , Amiloide , Insuficiência Cardíaca/diagnóstico , Imuno-Histoquímica , Proteínas Amiloidogênicas , Pré-Albumina , Neuropatias Amiloides Familiares/diagnóstico , Cardiomiopatias/diagnóstico , Cardiomiopatias/terapia
6.
Int J Mol Sci ; 25(5)2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38473811

RESUMO

Alzheimer's disease (AD) is the leading cause of dementia and is characterized by a presence of amyloid plaques, composed mostly of the amyloid-ß (Aß) peptides, in the brains of AD patients. The peptides are generated from the amyloid precursor protein (APP), which undergoes a sequence of cleavages, referred as trimming, performed by γ-secretase. Here, we investigated conformational changes in a series of ß-amyloid substrates (from less and more amyloidogenic pathways) in the active site of presenilin-1, the catalytic subunit of γ-secretase. The substrates are trimmed every three residues, finally leading to Aß40 and Aß42, which are the major components of amyloid plaques. To study conformational changes, we employed all-atom molecular dynamics simulations, while for unfolding, we used steered molecular dynamics simulations in an implicit membrane-water environment to accelerate changes. We have found substantial differences in the flexibility of extended C-terminal parts between more and less amyloidogenic pathway substrates. We also propose that the positively charged residues of presenilin-1 may facilitate the stretching and unfolding of substrates. The calculated forces and work/energy of pulling were exceptionally high for Aß40, indicating why trimming of this substrate is so infrequent.


Assuntos
Doença de Alzheimer , Secretases da Proteína Precursora do Amiloide , Humanos , Secretases da Proteína Precursora do Amiloide/metabolismo , Presenilina-1/metabolismo , Domínio Catalítico , Placa Amiloide , Peptídeos beta-Amiloides/metabolismo , Doença de Alzheimer/metabolismo
7.
Int J Mol Sci ; 25(5)2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38474051

RESUMO

Alzheimer's disease (AD), the leading cause of dementia, presents a significant global health challenge with no known cure to date. Central to our understanding of AD pathogenesis is the ß-amyloid cascade hypothesis, which underlies drug research and discovery efforts. Despite extensive studies, no animal models of AD have completely validated this hypothesis. Effective AD models are essential for accurately replicating key pathological features of the disease, notably the formation of ß-amyloid plaques and neurofibrillary tangles. These pathological markers are primarily driven by mutations in the amyloid precursor protein (APP) and presenilin 1 (PS1) genes in familial AD (FAD) and by tau protein mutations for the tangle pathology. Transgenic mice models have been instrumental in AD research, heavily relying on the overexpression of mutated APP genes to simulate disease conditions. However, these models do not entirely replicate the human condition of AD. This review aims to provide a comprehensive evaluation of the historical and ongoing research efforts in AD, particularly through the use of transgenic mice models. It is focused on the benefits gathered from these transgenic mice models in understanding ß-amyloid toxicity and the broader biological underpinnings of AD. Additionally, the review critically assesses the application of these models in the preclinical testing of new therapeutic interventions, highlighting the gap between animal models and human clinical realities. This analysis underscores the need for refinement in AD research methodologies to bridge this gap and enhance the translational value of preclinical studies.


Assuntos
Doença de Alzheimer , Camundongos , Animais , Humanos , Doença de Alzheimer/metabolismo , Camundongos Transgênicos , Modelos Animais de Doenças , Proteínas tau/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Presenilina-1/genética , Placa Amiloide/metabolismo
8.
Cells ; 13(5)2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38474412

RESUMO

Proximity-induced pharmacology (PIP) for amyloid-related diseases is a cutting-edge approach to treating conditions such as Alzheimer's disease and other forms of dementia. By bringing small molecules close to amyloid-related proteins, these molecules can induce a plethora of effects that can break down pathogenic proteins and reduce the buildup of plaques. One of the most promising aspects of this drug discovery modality is that it can be used to target specific types of amyloid proteins, such as the beta-amyloid protein that is commonly associated with Alzheimer's disease. This level of specificity could allow for more targeted and effective treatments. With ongoing research and development, it is hoped that these treatments can be refined and optimized to provide even greater benefits to patients. As our understanding of the underlying mechanisms of these diseases continues to grow, proximity-induced pharmacology treatments may become an increasingly important tool in the fight against dementia and other related conditions.


Assuntos
Doença de Alzheimer , Amiloidose , Humanos , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Placa Amiloide/metabolismo
9.
Mol Neurodegener ; 19(1): 25, 2024 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-38493185

RESUMO

Age-dependent accumulation of amyloid plaques in patients with sporadic Alzheimer's disease (AD) is associated with reduced amyloid clearance. Older microglia have a reduced ability to phagocytose amyloid, so phagocytosis of amyloid plaques by microglia could be regulated to prevent amyloid accumulation. Furthermore, considering the aging-related disruption of cell cycle machinery in old microglia, we hypothesize that regulating their cell cycle could rejuvenate them and enhance their ability to promote more efficient amyloid clearance. First, we used gene ontology analysis of microglia from young and old mice to identify differential expression of cyclin-dependent kinase inhibitor 2A (p16ink4a), a cell cycle factor related to aging. We found that p16ink4a expression was increased in microglia near amyloid plaques in brain tissue from patients with AD and 5XFAD mice, a model of AD. In BV2 microglia, small interfering RNA (siRNA)-mediated p16ink4a downregulation transformed microglia with enhanced amyloid phagocytic capacity through regulated the cell cycle and increased cell proliferation. To regulate microglial phagocytosis by gene transduction, we used poly (D,L-lactic-co-glycolic acid) (PLGA) nanoparticles, which predominantly target microglia, to deliver the siRNA and to control microglial reactivity. Nanoparticle-based delivery of p16ink4a siRNA reduced amyloid plaque formation and the number of aged microglia surrounding the plaque and reversed learning deterioration and spatial memory deficits. We propose that downregulation of p16ink4a in microglia is a promising strategy for the treatment of Alzheimer's disease.


Assuntos
Doença de Alzheimer , Idoso , Animais , Humanos , Camundongos , Doença de Alzheimer/metabolismo , Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Modelos Animais de Doenças , Camundongos Transgênicos , Microglia/metabolismo , Placa Amiloide/metabolismo , RNA Interferente Pequeno
10.
Int J Geriatr Psychiatry ; 39(3): e6076, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38488826

RESUMO

OBJECTIVES: The herbs in Tao Hong Si Wu Decoction (THSWD) are beneficial in the treatment of cognitive impairment. However, the underlying mechanisms of THSWD in treating diabetes-associated cognitive dysfunction (DACD) are not entirely explored. This study is aimed to investigate the therapeutic effects of THSWD in DACD model rats and the underlying mechanism. METHODS: Ultra-high-phase liquid chromatography was employed to identify the main compounds contained in the THSWD extract. DACD rat model was induced by feeding with a high-sugar and high-fat diet and injecting streptozotocin (35 mg/kg). DACD rats were gavaged with THSWD for 1 week. The learning and memory abilities of the rats were measured by using the Morris water maze. Western blotting was used to detect the changes in DACD rat targets. Statistical methods were used to evaluate the correlation between proteins. RESULTS: The results show that THSWD effectively reduced the escape latency, hippocampal neuron damage, glycosylated hemoglobin, type A1C, and blood lipid levels in DACD rats. Furthermore, DACD rats showed significantly increased amyloid precursor protein, ß-secretase, Aß1-40 , Aß1-42 , Tau phosphorylation, and advanced glycation end products (AGEs) expression. However, THSWD treatment can reverse this phenomenon. CONCLUSIONS: THSWD can improve the learning and memory abilities of DACD rats by inhibiting the expression of AEGs-AGE receptors pathway, which provides an experimental basis for the clinical application of THSWD. In addition, the experiment combines pharmacological and statistical methods, which offers a new perspective for the study of Chinese herbal medicine.


Assuntos
Disfunção Cognitiva , Diabetes Mellitus , Medicamentos de Ervas Chinesas , Humanos , Ratos , Animais , Medicamentos de Ervas Chinesas/uso terapêutico , Medicamentos de Ervas Chinesas/farmacologia , Placa Amiloide , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia
11.
J Transl Med ; 22(1): 291, 2024 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-38500108

RESUMO

BACKGROUND: Biologic TNF-α inhibitors (bTNFIs) can block cerebral TNF-α in Alzheimer's disease (AD) if these macromolecules can cross the blood-brain barrier (BBB). Thus, a model bTNFI, the extracellular domain of type II TNF-α receptor (TNFR), which can bind to and sequester TNF-α, was fused with a mouse transferrin receptor antibody (TfRMAb) to enable brain delivery via BBB TfR-mediated transcytosis. Previously, we found TfRMAb-TNFR to be protective in a mouse model of amyloidosis (APP/PS1) and tauopathy (PS19), and herein we investigated its effects in mice that combine both amyloidosis and tauopathy (3xTg-AD). METHODS: Eight-month-old female 3xTg-AD mice were injected intraperitoneally with saline (n = 11) or TfRMAb-TNFR (3 mg/kg; n = 11) three days per week for 12 weeks. Age-matched wild-type (WT) mice (n = 9) were treated similarly with saline. Brains were processed for immunostaining and high-resolution multiplex NanoString GeoMx spatial proteomics. RESULTS: We observed regional differences in proteins relevant to Aß, tau, and neuroinflammation in the hippocampus of 3xTg-AD mice compared with WT mice. From 64 target proteins studied using spatial proteomics, a comparison of the Aß-plaque bearing vs. plaque-free regions in the 3xTg-AD mice yielded 39 differentially expressed proteins (DEP) largely related to neuroinflammation (39% of DEP) and Aß and tau pathology combined (31% of DEP). Hippocampal spatial proteomics revealed that the majority of the proteins modulated by TfRMAb-TNFR in the 3xTg-AD mice were relevant to microglial function (⁓ 33%). TfRMAb-TNFR significantly reduced mature Aß plaques and increased Aß-associated microglia around larger Aß deposits in the 3xTg-AD mice. Further, TfRMAb-TNFR increased mature Aß plaque-associated microglial TREM2 in 3xTg-AD mice. CONCLUSION: Overall, despite the low visual Aß load in the 11-month-old female 3xTg-AD mice, our results highlight region-specific AD-relevant DEP in the hippocampus of these mice. Chronic TfRMAb-TNFR dosing modulated several DEP involved in AD pathology and showed a largely microglia-centric mechanism of action in the 3xTg-AD mice.


Assuntos
Doença de Alzheimer , Amiloidose , Produtos Biológicos , Camundongos , Feminino , Animais , Doença de Alzheimer/tratamento farmacológico , Fator de Necrose Tumoral alfa/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Doenças Neuroinflamatórias , Camundongos Transgênicos , Encéfalo/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Amiloidose/metabolismo , Amiloidose/patologia , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Anticorpos/metabolismo , Produtos Biológicos/metabolismo , Modelos Animais de Doenças
12.
JCI Insight ; 9(6)2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38516884

RESUMO

Substantial evidence suggests a role for immunotherapy in treating Alzheimer's disease (AD). While the precise pathophysiology of AD is incompletely understood, clinical trials of antibodies targeting aggregated forms of ß amyloid (Aß) have shown that reducing amyloid plaques can mitigate cognitive decline in patients with early-stage AD. Here, we describe what we believe to be a novel approach to target and degrade amyloid plaques by genetically engineering macrophages to express an Aß-targeting chimeric antigen receptor (CAR-Ms). When injected intrahippocampally, first-generation CAR-Ms have limited persistence and fail to significantly reduce plaque load, which led us to engineer next-generation CAR-Ms that secrete M-CSF and self-maintain without exogenous cytokines. Cytokine secreting "reinforced CAR-Ms" have greater survival in the brain niche and significantly reduce plaque load locally in vivo. These findings support CAR-Ms as a platform to rationally target, resorb, and degrade pathogenic material that accumulates with age, as exemplified by targeting Aß in AD.


Assuntos
Doença de Alzheimer , Receptores de Antígenos Quiméricos , Camundongos , Animais , Humanos , Camundongos Transgênicos , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Doença de Alzheimer/patologia , Citocinas/metabolismo , Macrófagos/metabolismo
13.
Sci Rep ; 14(1): 6287, 2024 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-38491154

RESUMO

The absence of a natural animal model is one of the main challenges in Alzheimer's disease research. Despite the challenges of using nonhuman primates in studies, these animals can bridge mouse models and humans, as nonhuman primates are phylogenetically closer to humans and can spontaneously develop AD-type pathology. The capuchin monkey, a New World primate, has recently attracted attention due to its skill in creating and using instruments. We analyzed one capuchin brain using structural 7 T MRI and performed a neuropathological evaluation of three animals. Alzheimer-type pathology was found in the two of the capuchins. Widespread ß-amyloid pathology was observed, mainly in focal deposits with variable morphology and a high density of mature plaques. Notably, plaque-associated dystrophic neurites associated with disruption of axonal transport and early cytoskeletal alteration were frequently found. Unlike in other species of New World monkeys, cerebral arterial angiopathy was not the predominant form of ß-amyloid pathology. Additionally, abnormal aggregates of hyperphosphorylated tau, resembling neurofibrillary pathology, were observed in the temporal and frontal cortex. Astrocyte hypertrophy surrounding plaques was found, suggesting a neuroinflammatory response. These findings indicate that aged capuchin monkeys can spontaneously develop Alzheimer-type pathology, indicating that they may be an advantageous animal model for research in Alzheimer's disease.


Assuntos
Doença de Alzheimer , Cebinae , Humanos , Animais , Camundongos , Idoso , Doença de Alzheimer/patologia , Cebus , Haplorrinos , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Placa Amiloide/patologia , Proteínas tau/metabolismo
14.
Sci Adv ; 10(12): eadk9884, 2024 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-38507480

RESUMO

Molecular chaperones are protective in neurodegenerative diseases by preventing protein misfolding and aggregation, such as extracellular amyloid plaques and intracellular tau neurofibrillary tangles in Alzheimer's disease (AD). In addition, AD is characterized by an increase in astrocyte reactivity. The chaperone HSPB1 has been proposed as a marker for reactive astrocytes; however, its astrocytic functions in neurodegeneration remain to be elucidated. Here, we identify that HSPB1 is secreted from astrocytes to exert non-cell-autonomous protective functions. We show that in human AD brain, HSPB1 levels increase in astrocytes that cluster around amyloid plaques, as well as in the adjacent extracellular space. Moreover, in conditions that mimic an inflammatory reactive response, astrocytes increase HSPB1 secretion. Concomitantly, astrocytes and neurons can uptake astrocyte-secreted HSPB1, which is accompanied by an attenuation of the inflammatory response in reactive astrocytes and reduced pathological tau inclusions. Our findings highlight a protective mechanism in disease conditions that encompasses the secretion of a chaperone typically regarded as intracellular.


Assuntos
Doença de Alzheimer , Astrócitos , Humanos , Astrócitos/metabolismo , Proteínas tau/metabolismo , Placa Amiloide/patologia , Neuroproteção , Chaperonas Moleculares/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Proteínas de Choque Térmico/metabolismo
15.
J Neurosci Res ; 102(3): e25295, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38515329

RESUMO

Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia, characterized by deposition of extracellular amyloid-beta (Aß) aggregates and intraneuronal hyperphosphorylated Tau. Many AD risk genes, identified in genome-wide association studies (GWAS), are expressed in microglia, the innate immune cells of the central nervous system. Specific subtypes of microglia emerged in relation to AD pathology, such as disease-associated microglia (DAMs), which increased in number with age in amyloid mouse models and in human AD cases. However, the initial transcriptional changes in these microglia in response to amyloid are still unknown. Here, to determine early changes in microglia gene expression, hippocampal microglia from male APPswe/PS1dE9 (APP/PS1) mice and wild-type littermates were isolated and analyzed by RNA sequencing (RNA-seq). By bulk RNA-seq, transcriptomic changes were detected in hippocampal microglia from 6-months-old APP/PS1 mice. By performing single-cell RNA-seq of CD11c-positive and negative microglia from 6-months-old APP/PS1 mice and analysis of the transcriptional trajectory from homeostatic to CD11c-positive microglia, we identified a set of genes that potentially reflect the initial response of microglia to Aß.


Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Humanos , Camundongos , Masculino , Animais , Lactente , Microglia/metabolismo , Camundongos Transgênicos , Estudo de Associação Genômica Ampla , Doenças Neurodegenerativas/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Transcriptoma , Placa Amiloide , Modelos Animais de Doenças , Precursor de Proteína beta-Amiloide/genética , Presenilina-1/genética
16.
ACS Chem Neurosci ; 15(4): 877-888, 2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38299453

RESUMO

Lipid dysregulations have been critically implicated in Alzheimer's disease (AD) pathology. Chemical analysis of amyloid-ß (Aß) plaque pathology in transgenic AD mouse models has demonstrated alterations in the microenvironment in the direct proximity of Aß plaque pathology. In mouse studies, differences in lipid patterns linked to structural polymorphism among Aß pathology, such as diffuse, immature, and mature fibrillary aggregates, have also been reported. To date, no comprehensive analysis of neuronal lipid microenvironment changes in human AD tissue has been performed. Here, for the first time, we leverage matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) through a high-speed and spatial resolution commercial time-of-light instrument, as well as a high-mass-resolution in-house-developed orbitrap system to characterize the lipid microenvironment in postmortem human brain tissue from AD patients carrying Presenilin 1 mutations (PSEN1) that lead to familial forms of AD (fAD). Interrogation of the spatially resolved MSI data on a single Aß plaque allowed us to verify nearly 40 sphingolipid and phospholipid species from diverse subclasses being enriched and depleted, in relation to the Aß deposits. This included monosialo-gangliosides (GM), ceramide monohexosides (HexCer), ceramide-1-phosphates (CerP), ceramide phosphoethanolamine conjugates (PE-Cer), sulfatides (ST), as well as phosphatidylinositols (PI), phosphatidylethanolamines (PE), and phosphatidic acid (PA) species (including Lyso-forms). Indeed, many of the sphingolipid species overlap with the species previously seen in transgenic AD mouse models. Interestingly, in comparison to the animal studies, we observed an increased level of localization of PE and PI species containing arachidonic acid (AA). These findings are highly relevant, demonstrating for the first time Aß plaque pathology-related alteration in the lipid microenvironment in humans. They provide a basis for the development of potential lipid biomarkers for AD characterization and insight into human-specific molecular pathway alterations.


Assuntos
Doença de Alzheimer , Humanos , Camundongos , Animais , Doença de Alzheimer/metabolismo , Cromatografia Gasosa-Espectrometria de Massas , Peptídeos beta-Amiloides/metabolismo , Camundongos Transgênicos , Encéfalo/metabolismo , Esfingolipídeos/metabolismo , Placa Amiloide/metabolismo , Ceramidas/metabolismo , Modelos Animais de Doenças , Precursor de Proteína beta-Amiloide/metabolismo
17.
Biomolecules ; 14(2)2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38397402

RESUMO

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by amyloid-beta (Aß) plaques and tau neurofibrillary tangles (NFT). Modelling aspects of AD is challenging due to its complex multifactorial etiology and pathology. The present study aims to establish a cost-effective and rapid method to model the two primary pathologies in organotypic brain slices. Coronal hippocampal brain slices (150 µm) were generated from postnatal (day 8-10) C57BL6 wild-type mice and cultured for 9 weeks. Collagen hydrogels containing either an empty load or a mixture of human Aß42 and P301S aggregated tau were applied to the slices. The media was further supplemented with various intracellular pathway modulators or heavy metals to augment the appearance of Aß plaques and tau NFTs, as assessed by immunohistochemistry. Immunoreactivity for Aß and tau was significantly increased in the ventral areas in slices with a mixture of human Aß42 and P301S aggregated tau compared to slices with empty hydrogels. Aß plaque- and tau NFT-like pathologies could be induced independently in slices. Heavy metals (aluminum, lead, cadmium) potently augmented Aß plaque-like pathology, which developed intracellularly prior to cell death. Intracellular pathway modulators (scopolamine, wortmannin, MHY1485) significantly boosted tau NFT-like pathologies. A combination of nanomolar concentrations of scopolamine, wortmannin, MHY1485, lead, and cadmium in the media strongly increased Aß plaque- and tau NFT-like immunoreactivity in ventral areas compared to the slices with non-supplemented media. The results highlight that we could harness the potential of the collagen hydrogel-based spreading of human Aß42 and P301S aggregated tau, along with pharmacological manipulation, to produce pathologies relevant to AD. The results offer a novel ex vivo organotypic slice model to investigate AD pathologies with potential applications for screening drugs or therapies in the future.


Assuntos
Doença de Alzheimer , Camundongos , Animais , Humanos , Doença de Alzheimer/metabolismo , Proteínas tau/metabolismo , Cádmio/metabolismo , Wortmanina/metabolismo , Camundongos Transgênicos , Peptídeos beta-Amiloides/metabolismo , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Encéfalo/metabolismo , Placa Amiloide/complicações , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Colágeno/metabolismo , Hidrogéis/metabolismo , Derivados da Escopolamina/metabolismo
18.
J Alzheimers Dis ; 97(4): 1939-1950, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38339931

RESUMO

Background: Vitamin D has neuroprotective and immunomodulating functions that may impact glial cell function in the brain. Previously, we reported molecular and behavioral changes caused by deficiency and supplementation of vitamin D in an Alzheimer's disease (AD) mouse model. Recent studies have highlighted reactive astrocytes as a new therapeutic target for AD treatment. However, the mechanisms underlying the therapeutic effects of vitamin D on the glial cells of AD remain unclear. Objective: To investigate the potential association between vitamin D deficiency/supplementation and the pathological progression of AD, including amyloid-ß (Aß) pathology and reactive astrogliosis. Methods: Transgenic hemizygous 5XFAD male mice were subjected to different dietary interventions and intraperitoneal vitamin D injections to examine the effects of vitamin D deficiency and supplementation on AD. Brain tissue was then analyzed using immunohistochemistry for Aß plaques, microglia, and astrocytes, with quantifications performed via ImageJ software. Results: Our results demonstrated that vitamin D deficiency exacerbated Aß plaque formation and increased GABA-positive reactive astrocytes in AD model mice, while vitamin D supplementation ameliorated these effects, leading to a reduction in Aß plaques and GABA-positive astrocytes. Conclusions: Our findings highlight the significant impact of vitamin D status on Aß pathology and reactive astrogliosis, underscoring its potential role in the prevention and treatment of AD. This study provides the first in vivo evidence of the association between vitamin D and reactive astrogliosis in AD model mice, indicating the potential for targeting vitamin D levels as a novel therapeutic approach for AD.


Assuntos
Doença de Alzheimer , Deficiência de Vitamina D , Masculino , Camundongos , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Astrócitos/patologia , Vitamina D/uso terapêutico , Gliose/tratamento farmacológico , Gliose/patologia , Peptídeos beta-Amiloides/uso terapêutico , Camundongos Transgênicos , Placa Amiloide/patologia , Vitaminas/farmacologia , Vitaminas/uso terapêutico , Ácido gama-Aminobutírico , Modelos Animais de Doenças
19.
Mol Neurodegener ; 19(1): 18, 2024 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-38365827

RESUMO

It has recently become well-established that there is a connection between Alzheimer's disease pathology and gut microbiome dysbiosis. We have previously demonstrated that antibiotic-mediated gut microbiota perturbations lead to attenuation of Aß deposition, phosphorylated tau accumulation, and disease-associated glial cell phenotypes in a sex-dependent manner. In this regard, we were intrigued by the finding that a marine-derived oligosaccharide, GV-971, was reported to alter gut microbiota and reduce Aß amyloidosis in the 5XFAD mouse model that were treated at a point when Aß burden was near plateau levels. Utilizing comparable methodologies, but with distinct technical and temporal features, we now report on the impact of GV-971 on gut microbiota, Aß amyloidosis and microglial phenotypes in the APPPS1-21 model, studies performed at the University of Chicago, and independently in the 5X FAD model, studies performed at Washington University, St. Louis.Methods To comprehensively characterize the effects of GV-971 on the microbiota-microglia-amyloid axis, we conducted two separate investigations at independent institutions. There was no coordination of the experimental design or execution between the two laboratories. Indeed, the two laboratories were not aware of each other's experiments until the studies were completed. Male and female APPPS1-21 mice were treated daily with 40, 80, or 160 mg/kg of GV-971 from 8, when Aß burden was detectable upto 12 weeks of age when Aß burden was near maximal levels. In parallel, and to corroborate existing published studies and further investigate sex-related differences, male and female 5XFAD mice were treated daily with 100 mg/kg of GV-971 from 7 to 9 months of age when Aß burden was near peak levels. Subsequently, the two laboratories independently assessed amyloid-ß deposition, metagenomic, and neuroinflammatory profiles. Finally, studies were initiated at the University of Chicago to evaluate the metabolites in cecal tissue from vehicle and GV-971-treated 5XFAD mice.Results These studies showed that independent of the procedural differences (dosage, timing and duration of treatment) between the two laboratories, cerebral amyloidosis was reduced primarily in male mice, independent of strain. We also observed sex-specific microbiota differences following GV-971 treatment. Interestingly, GV-971 significantly altered multiple overlapping bacterial species at both institutions. Moreover, we discovered that GV-971 significantly impacted microbiome metabolism, particularly by elevating amino acid production and influencing the tryptophan pathway. The metagenomics and metabolomics changes correspond with notable reductions in peripheral pro-inflammatory cytokine and chemokine profiles. Furthermore, GV-971 treatment dampened astrocyte and microglia activation, significantly decreasing plaque-associated reactive microglia while concurrently increasing homeostatic microglia only in male mice. Bulk RNAseq analysis unveiled sex-specific changes in cerebral cortex transcriptome profiles, but most importantly, the transcriptome changes in the GV-971-treated male group revealed the involvement of microglia and inflammatory responses.Conclusions In conclusion, these studies demonstrate the connection between the gut microbiome, neuroinflammation, and Alzheimer's disease pathology while highlighting the potential therapeutic effect of GV-971. GV-971 targets the microbiota-microglia-amyloid axis, leading to the lowering of plaque pathology and neuroinflammatory signatures in a sex-dependent manner when given at the onset of Aß deposition or when given after Aß deposition is already at higher levels.


Assuntos
Doença de Alzheimer , Amiloidose , Microbioma Gastrointestinal , Humanos , Camundongos , Masculino , Feminino , Animais , Doença de Alzheimer/metabolismo , Microglia/metabolismo , Camundongos Transgênicos , Amiloidose/metabolismo , Peptídeos beta-Amiloides/metabolismo , Placa Amiloide/patologia , Amiloide/metabolismo , Proteínas Amiloidogênicas/metabolismo , Modelos Animais de Doenças
20.
Transl Vis Sci Technol ; 13(2): 11, 2024 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-38359019

RESUMO

Background: Transthyretin amyloidosis (ATTR) is a significant cause of cardiomyopathy and other morbidities in the elderly and Black Americans. ATTR can be treated with new disease-modifying therapies, but large shortfalls exist in its diagnosis. The objective of this study was to test whether TTR amyloid can be detected and imaged in the conjunctiva using a novel small-molecule fluorescent ocular tracer, with the implication that ATTR might be diagnosable by a simple eye examination. Methods: Three approaches were used in this study. First, AMDX-9101 was incubated with in vitro aggregated TTR protein, and changes in its excitation and emission spectra were quantified. Second, a cadaver eye from a patient with familial amyloid polyneuropathy type II TTR mutation and a vitrectomy sample from an hATTR patient were incubated with AMDX-9101 and counterstained with Congo Red and antibodies to TTR to determine whether AMDX-9101 labels disease-related TTR amyloid deposits in human conjunctiva and eye. Last, imaging of in vitro aggregated TTR amyloid labeled with AMDX-9101 was tested in a porcine ex vivo model, using a widely available clinical ophthalmic imaging device. Results: AMDX-9101 hyper-fluoresced in the presence of TTR amyloid in vitro, labeled TTR amyloid deposits in postmortem human conjunctiva and other ocular tissues and could be detected under the conjunctiva of a porcine eye using commercially available ophthalmic imaging equipment. Conclusions: AMDX-9101 enabled detection of TTR amyloid in the conjunctiva, and the fluorescent binding signal can be visualized using commercially available ophthalmic imaging equipment. Translational Relevance: AMDX-9101 detection of TTR amyloid may provide a potential new and noninvasive test for ATTR that could lead to earlier ATTR diagnosis, as well as facilitate development of new therapeutics.


Assuntos
Neuropatias Amiloides Familiares , Placa Amiloide , Humanos , Animais , Suínos , Idoso , Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/tratamento farmacológico , Neuropatias Amiloides Familiares/genética , Vermelho Congo/uso terapêutico , Túnica Conjuntiva
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