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1.
Alzheimers Res Ther ; 16(1): 121, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38831312

RESUMO

BACKGROUND: Beta-amyloid (Aß) deposition in the brain parenchyma is a crucial initiating step in the amyloid cascade hypothesis of Alzheimer's disease (AD) pathology. Furthermore, dysfunction of plaque-associated microglia, also known as disease-associated microglia (DAM) has been reported to accelerate Aß deposition and cognitive impairment. Our previous research demonstrated that intermittent hypoxia training (IHT) improved AD pathology by upregulating autophagy in DAM, thereby enhancing oligomeric Aß (oAß) clearance. Considering that oAß internalization is the initial stage of oAß clearance, this study focused on the IHT mechanism involved in upregulating Aß uptake by DAM. METHODS: IHT was administered to 8-month-old APP/PS1 mice or 6-month-old microglial vacuolar protein sorting 35 (VPS35) knockout mice in APP/PS1 background (MG VPS35 KO: APP/PS1) for 28 days. After the IHT, the spatial learning-memory capacity of the mice was assessed. Additionally, AD pathology was determined by estimating the nerve fiber and synapse density, Aß plaque deposition, and Aß load in the brain. A model of Aß-exposed microglia was constructed and treated with IHT to explore the related mechanism. Finally, triggering receptor expressed on myeloid cells 2 (TREM2) intracellular recycling and Aß internalization were measured using a fluorescence tracing technique. RESULTS: Our results showed that IHT ameliorated cognitive function and Aß pathology. In particular, IHT enhanced Aß endocytosis by augmenting the intracellular transport function of microglial TREM2, thereby contributing to Aß clearance. Furthermore, IHT specifically upregulated VPS35 in DAM, the primary cause for the enhanced intracellular recycling of TREM2. IHT lost ameliorative effect on Aß pathology in MG VPS35 KO: APP/PS1 mice brain. Lastly, the IHT mechanism of VPS35 upregulation in DAM was mediated by the transcriptional regulation of VPS35 by transcription factor EB (TFEB). CONCLUSION: IHT enhances Aß endocytosis in DAM by upregulating VPS35-dependent TREM2 recycling, thereby facilitating oAß clearance and mitigation of Aß pathology. Moreover, the transcriptional regulation of VPS35 by TFEB demonstrates a close link between endocytosis and autophagy in microglia. Our study further elucidates the IHT mechanism in improving AD pathology and provides evidence supporting the potential application of IHT as a complementary therapy for AD.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Endocitose , Glicoproteínas de Membrana , Microglia , Placa Amiloide , Receptores Imunológicos , Animais , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/genética , Microglia/metabolismo , Camundongos , Receptores Imunológicos/metabolismo , Receptores Imunológicos/genética , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/genética , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Peptídeos beta-Amiloides/metabolismo , Endocitose/fisiologia , Proteínas de Transporte Vesicular/metabolismo , Proteínas de Transporte Vesicular/genética , Camundongos Transgênicos , Hipóxia/metabolismo , Camundongos Knockout , Modelos Animais de Doenças , Masculino , Encéfalo/metabolismo , Encéfalo/patologia , Camundongos Endogâmicos C57BL
2.
BMJ Ment Health ; 27(1)2024 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-38796179

RESUMO

QUESTION: Does neurodegenerative disease underlie the increased rate of dementia observed in older people with schizophrenia? Several studies have reported a higher prevalence of dementia in people with schizophrenia compared with the general population. This may reflect a higher risk of developing neurodegenerative diseases such as vascular dementia or Alzheimer's disease (AD). Alternatively, this may reflect non-pathological, age-related cognitive decline in a population with low cognitive reserve. STUDY SELECTION AND ANALYSIS: We reviewed papers that compared postmortem findings, hippocampal MRI volume or cerebrospinal fluid (CSF) markers of AD, between patients with schizophrenia with evidence of cognitive impairment (age ≥45 years) with controls. We subsequently performed a meta-analysis of postmortem studies that compared amyloid-ß plaques (APs) or neurofibrillary tangles (NFTs) in cognitively impaired patients with schizophrenia to normal controls or an AD group. FINDINGS: No studies found a significant increase of APs or NFTs in cognitively impaired patients with schizophrenia compared with controls. All postmortem studies that compared APs or NFTs in patients with schizophrenia to an AD group found significantly more APs or NFTs in AD. No studies found a significant differences in CSF total tau or phosphorylated tau between patients with schizophrenia and controls. The two studies which compared CSF Aß42 between patients with schizophrenia and controls found significantly decreased CSF Aß42 in schizophrenia compared with controls. Hippocampal volume findings were mixed. CONCLUSIONS: Studies have not found higher rates of AD-related pathology in cognitively impaired individuals with schizophrenia compared with controls. Higher rates of dementia identified in population studies may reflect a lack of specificity in clinical diagnostic tools used to diagnose dementia.


Assuntos
Biomarcadores , Esquizofrenia , Humanos , Esquizofrenia/líquido cefalorraquidiano , Esquizofrenia/patologia , Biomarcadores/líquido cefalorraquidiano , Doenças Neurodegenerativas/líquido cefalorraquidiano , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/diagnóstico por imagem , Doenças Neurodegenerativas/diagnóstico , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/patologia , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Peptídeos beta-Amiloides/metabolismo , Emaranhados Neurofibrilares/patologia , Placa Amiloide/patologia , Placa Amiloide/diagnóstico por imagem
3.
Mol Neurodegener ; 19(1): 42, 2024 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-38802940

RESUMO

Microglia play diverse pathophysiological roles in Alzheimer's disease (AD), with genetic susceptibility factors skewing microglial cell function to influence AD risk. CD33 is an immunomodulatory receptor associated with AD susceptibility through a single nucleotide polymorphism that modulates mRNA splicing, skewing protein expression from a long protein isoform (CD33M) to a short isoform (CD33m). Understanding how human CD33 isoforms differentially impact microglial cell function in vivo has been challenging due to functional divergence of CD33 between mice and humans. We address this challenge by studying transgenic mice expressing either of the human CD33 isoforms crossed with the 5XFAD mouse model of amyloidosis and find that human CD33 isoforms have opposing effects on the response of microglia to amyloid-ß (Aß) deposition. Mice expressing CD33M have increased Aß levels, more diffuse plaques, fewer disease-associated microglia, and more dystrophic neurites compared to 5XFAD control mice. Conversely, CD33m promotes plaque compaction and microglia-plaque contacts, and minimizes neuritic plaque pathology, highlighting an AD protective role for this isoform. Protective phenotypes driven by CD33m are detected at an earlier timepoint compared to the more aggressive pathology in CD33M mice that appears at a later timepoint, suggesting that CD33m has a more prominent impact on microglia cell function at earlier stages of disease progression. In addition to divergent roles in modulating phagocytosis, scRNAseq and proteomics analyses demonstrate that CD33m+ microglia upregulate nestin, an intermediate filament involved in cell migration, at plaque contact sites. Overall, our work provides new functional insights into how CD33, as a top genetic susceptibility factor for AD, modulates microglial cell function.


Assuntos
Doença de Alzheimer , Modelos Animais de Doenças , Camundongos Transgênicos , Microglia , Isoformas de Proteínas , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico , Animais , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Microglia/metabolismo , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Humanos , Camundongos , Isoformas de Proteínas/metabolismo , Peptídeos beta-Amiloides/metabolismo , Placa Amiloide/metabolismo , Placa Amiloide/patologia
4.
Nat Commun ; 15(1): 3996, 2024 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-38734693

RESUMO

SPI1 was recently reported as a genetic risk factor for Alzheimer's disease (AD) in large-scale genome-wide association studies. However, it is unknown whether SPI1 should be downregulated or increased to have therapeutic benefits. To investigate the effect of modulating SPI1 levels on AD pathogenesis, we performed extensive biochemical, histological, and transcriptomic analyses using both Spi1-knockdown and Spi1-overexpression mouse models. Here, we show that the knockdown of Spi1 expression significantly exacerbates insoluble amyloid-ß (Aß) levels, amyloid plaque deposition, and gliosis. Conversely, overexpression of Spi1 significantly ameliorates these phenotypes and dystrophic neurites. Further mechanistic studies using targeted and single-cell transcriptomics approaches demonstrate that altered Spi1 expression modulates several pathways, such as immune response pathways and complement system. Our data suggest that transcriptional reprogramming by targeting transcription factors, like Spi1, might hold promise as a therapeutic strategy. This approach could potentially expand the current landscape of druggable targets for AD.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Amiloidose , Modelos Animais de Doenças , Proteínas Proto-Oncogênicas , Transcriptoma , Animais , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Camundongos , Amiloidose/genética , Amiloidose/metabolismo , Amiloidose/patologia , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas/genética , Fenótipo , Camundongos Transgênicos , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Placa Amiloide/genética , Humanos , Masculino , Camundongos Endogâmicos C57BL , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Transativadores
5.
Int J Mol Sci ; 25(9)2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38731870

RESUMO

Transcranial magneto-acoustic stimulation (TMAS), which is characterized by high spatiotemporal resolution and high penetrability, is a non-invasive neuromodulation technology based on the magnetic-acoustic coupling effect. To reveal the effects of TMAS treatment on amyloid-beta (Aß) plaque and synaptic plasticity in Alzheimer's disease, we conducted a comparative analysis of TMAS and transcranial ultrasound stimulation (TUS) based on acoustic effects in 5xFAD mice and BV2 microglia cells. We found that the TMAS-TUS treatment effectively reduced amyloid plaque loads and plaque-associated neurotoxicity. Additionally, TMAS-TUS treatment ameliorated impairments in long-term memory formation and long-term potentiation. Moreover, TMAS-TUS treatment stimulated microglial proliferation and migration while enhancing the phagocytosis and clearance of Aß. In 5xFAD mice with induced microglial exhaustion, TMAS-TUS treatment-mediated Aß plaque reduction, synaptic rehabilitation improvement, and the increase in phospho-AKT levels were diminished. Overall, our study highlights that stimulation of hippocampal microglia by TMAS treatment can induce anti-cognitive impairment effects via PI3K-AKT signaling, providing hope for the development of new strategies for an adjuvant therapy for Alzheimer's disease.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Microglia , Placa Amiloide , Animais , Microglia/metabolismo , Camundongos , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/terapia , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Estimulação Magnética Transcraniana/métodos , Estimulação Acústica , Camundongos Transgênicos , Modelos Animais de Doenças , Sinapses/metabolismo , Hipocampo/metabolismo , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Plasticidade Neuronal , Potenciação de Longa Duração , Transdução de Sinais
6.
Int J Mol Sci ; 25(9)2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38732223

RESUMO

Alzheimer's disease (AD) is characterized by a loss of neurons in the cortex and subcortical regions. Previously, we showed that the progressive degeneration of subcortical monoaminergic (MAergic) neurons seen in human AD is recapitulated in the APPswe/PS1ΔE9 (APP/PS) transgenic mouse model. Because degeneration of cholinergic (Ach) neurons is also a prominent feature of AD, we examined the integrity of the Ach system in the APP/PS model. The overall density of Ach fibers is reduced in APP/PS1 mice at 12 and 18 months of age but not at 4 months of age. Analysis of basal forebrain Ach neurons shows no loss of Ach neurons in the APP/PS model. Thus, since MAergic systems show overt cell loss at 18 months of age, the Ach system is less vulnerable to neurodegeneration in the APP/PS1 model. We also examined whether the proximity to Aß deposition affected the degeneration of Ach and 5-HT afferents. We found that the areas closer to the edges of compact Aß deposits exhibit a more severe loss of afferents than the areas that are more distal to Aß deposits. Collectively, the results indicate that the APP/PS model recapitulates the degeneration of multiple subcortical neurotransmitter systems, including the Ach system. In addition, the results indicate that Aß deposits cause global as well as local toxicity to subcortical afferents.


Assuntos
Doença de Alzheimer , Precursor de Proteína beta-Amiloide , Neurônios Colinérgicos , Modelos Animais de Doenças , Placa Amiloide , Presenilina-1 , Animais , Humanos , Camundongos , Doença de Alzheimer/patologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Neurônios Colinérgicos/metabolismo , Neurônios Colinérgicos/patologia , Camundongos Transgênicos , Placa Amiloide/patologia , Placa Amiloide/metabolismo , Presenilina-1/genética , Presenilina-1/metabolismo
7.
Brain Res Bull ; 212: 110969, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38705540

RESUMO

Alzheimer's disease (AD) stands as the most prevalent neurodegenerative condition worldwide, and its correlation with microglial function is notably significant. Dl-3-n-butylphthalide (NBP), derived from the seeds of Apium graveolens L. (Chinese celery), has demonstrated the capacity to diminish Aß levels in the brain tissue of Alzheimer's transgenic mice. Despite this, its connection to neuroinflammation and microglial phagocytosis, along with the specific molecular mechanism involved, remains undefined. In this study, NBP treatment exhibited a substantial improvement in learning deficits observed in AD transgenic mice (APP/PS1 transgenic mice). Furthermore, NBP treatment significantly mitigated the total cerebral Aß plaque deposition. This effect was attributed to the heightened presence of activated microglia surrounding Aß plaques and an increase in microglial phagocytosis of Aß plaques. Transcriptome sequencing analysis unveiled the potential involvement of the AGE (advanced glycation end products) -RAGE (receptor for AGE) signaling pathway in NBP's impact on APP/PS1 mice. Subsequent investigation disclosed a reduction in the secretion of AGEs, RAGE, and proinflammatory factors within the hippocampus and cortex of NBP-treated APP/PS1 mice. In summary, NBP alleviates cognitive impairment by augmenting the number of activated microglia around Aß plaques and ameliorating AGE-RAGE-mediated neuroinflammation. These findings underscore the related mechanism of the crucial neuroprotective roles of microglial phagocytosis and anti-inflammation in NBP treatment for AD, offering a potential therapeutic target for the disease.


Assuntos
Doença de Alzheimer , Benzofuranos , Camundongos Transgênicos , Microglia , Fagocitose , Receptor para Produtos Finais de Glicação Avançada , Animais , Microglia/efeitos dos fármacos , Microglia/metabolismo , Benzofuranos/farmacologia , Camundongos , Fagocitose/efeitos dos fármacos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Transdução de Sinais/efeitos dos fármacos , Masculino , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Inflamação/metabolismo , Inflamação/tratamento farmacológico , Modelos Animais de Doenças , Presenilina-1/genética , Presenilina-1/metabolismo , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Placa Amiloide/tratamento farmacológico , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/metabolismo
8.
Alzheimers Res Ther ; 16(1): 101, 2024 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-38711159

RESUMO

BACKGROUND: In Alzheimer's disease (AD), microglia surround extracellular plaques and mount a sustained inflammatory response, contributing to the pathogenesis of the disease. Identifying approaches to specifically target plaque-associated microglia (PAMs) without interfering in the homeostatic functions of non-plaque associated microglia would afford a powerful tool and potential therapeutic avenue. METHODS: Here, we demonstrated that a systemically administered nanomedicine, hydroxyl dendrimers (HDs), can cross the blood brain barrier and are preferentially taken up by PAMs in a mouse model of AD. As proof of principle, to demonstrate biological effects in PAM function, we treated the 5xFAD mouse model of amyloidosis for 4 weeks via systemic administration (ip, 2x weekly) of HDs conjugated to a colony stimulating factor-1 receptor (CSF1R) inhibitor (D-45113). RESULTS: Treatment resulted in significant reductions in amyloid-beta (Aß) and a stark reduction in the number of microglia and microglia-plaque association in the subiculum and somatosensory cortex, as well as a downregulation in microglial, inflammatory, and synaptic gene expression compared to vehicle treated 5xFAD mice. CONCLUSIONS: This study demonstrates that systemic administration of a dendranib may be utilized to target and modulate PAMs.


Assuntos
Doença de Alzheimer , Dendrímeros , Modelos Animais de Doenças , Camundongos Transgênicos , Microglia , Placa Amiloide , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Placa Amiloide/tratamento farmacológico , Placa Amiloide/patologia , Camundongos , Peptídeos beta-Amiloides/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Humanos
9.
Sci Adv ; 10(22): eadl1123, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38809977

RESUMO

Immunosenescence contributes to systematic aging and plays a role in the pathogenesis of Alzheimer's disease (AD). Therefore, the objective of this study was to investigate the potential of immune rejuvenation as a therapeutic strategy for AD. To achieve this, the immune systems of aged APP/PS1 mice were rejuvenated through young bone marrow transplantation (BMT). Single-cell RNA sequencing revealed that young BMT restored the expression of aging- and AD-related genes in multiple cell types within blood immune cells. The level of circulating senescence-associated secretory phenotype proteins was decreased following young BMT. Notably, young BMT resulted in a significant reduction in cerebral Aß plaque burden, neuronal degeneration, neuroinflammation, and improvement of behavioral deficits in aged APP/PS1 mice. The ameliorated cerebral amyloidosis was associated with an enhanced Aß clearance of peripheral monocytes. In conclusion, our study provides evidence that immune system rejuvenation represents a promising therapeutic approach for AD.


Assuntos
Doença de Alzheimer , Modelos Animais de Doenças , Rejuvenescimento , Animais , Doença de Alzheimer/terapia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/imunologia , Camundongos , Camundongos Transgênicos , Transplante de Medula Óssea , Comportamento Animal , Peptídeos beta-Amiloides/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Placa Amiloide/patologia , Placa Amiloide/metabolismo , Envelhecimento/imunologia , Humanos
10.
Biomed Pharmacother ; 175: 116616, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38723516

RESUMO

Fluorescent probes are a powerful tool for imaging amyloid ß (Aß) plaques, the hallmark of Alzheimer's disease (AD). Herein, we report the synthesis and comprehensive characterization of 21 novel probes as well as their optical properties and binding affinities to Aß fibrils. One of these dyes, 1Ae, exhibited several improvements over FDDNP, an established biomarker for Aß- and Tau-aggregates. First, 1Ae had large Stokes shifts (138-213 nm) in various solvents, thereby reducing self-absorption. With a high quantum yield ratio (φ(dichloromethane/methanol) = 104), 1Ae also ensures minimal background emission in aqueous environments and high sensitivity. In addition, compound 1Ae exhibited low micromolar binding affinity to Aß fibrils in vitro (Kd = 1.603 µM), while increasing fluorescence emission (106-fold) compared to emission in buffer alone. Importantly, the selective binding of 1Ae to Aß1-42 fibrils was confirmed by an in cellulo assay, supported by ex vivo fluorescence microscopy of 1Ae on postmortem AD brain sections, allowing unequivocal identification of Aß plaques. The intermolecular interactions of fluorophores with Aß were elucidated by docking studies and molecular dynamics simulations. Density functional theory calculations revealed the unique photophysics of these rod-shaped fluorophores, with a twisted intramolecular charge transfer (TICT) excited state. These results provide valuable insights into the future application of such probes as potential diagnostic tools for AD in vitro and ex vivo such as determination of Aß1-42 in cerebrospinal fluid or blood.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Corantes Fluorescentes , Doença de Alzheimer/metabolismo , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Humanos , Corantes Fluorescentes/química , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/líquido cefalorraquidiano , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/diagnóstico por imagem , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Microscopia de Fluorescência/métodos
11.
ACS Chem Neurosci ; 15(10): 2058-2069, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38652895

RESUMO

Amyloid plaques composed of fibrils of misfolded Aß peptides are pathological hallmarks of Alzheimer's disease (AD). Aß fibrils are polymorphic in their tertiary and quaternary molecular structures. This structural polymorphism may carry different pathologic potencies and can putatively contribute to clinical phenotypes of AD. Therefore, mapping of structural polymorphism of Aß fibrils and structural evolution over time is valuable to understanding disease mechanisms. Here, we investigated how Aß fibril structures in situ differ in Aß plaque of different mouse models expressing familial mutations in the AßPP gene. We imaged frozen brains with a combination of conformation-sensitive luminescent conjugated oligothiophene (LCO) ligands and Aß-specific antibodies. LCO fluorescence mapping revealed that mouse models APP23, APPPS1, and AppNL-F have different fibril structures within Aß-amyloid plaques depending on the AßPP-processing genotype. Co-staining with Aß-specific antibodies showed that individual plaques from APP23 mice expressing AßPP Swedish mutation have two distinct fibril polymorph regions of core and corona. The plaque core is predominantly composed of compact Aß40 fibrils, and the corona region is dominated by diffusely packed Aß40 fibrils. Conversely, the AßPP knock-in mouse AppNL-F, expressing the AßPP Iberian mutation along with Swedish mutation has tiny, cored plaques consisting mainly of compact Aß42 fibrils, vastly different from APP23 even at elevated age up to 21 months. Age-dependent polymorph rearrangement of plaque cores observed for APP23 and APPPS1 mice >12 months, appears strongly promoted by Aß40 and was hence minuscule in AppNL-F. These structural studies of amyloid plaques in situ can map disease-relevant fibril polymorph distributions to guide the design of diagnostic and therapeutic molecules.


Assuntos
Peptídeos beta-Amiloides , Precursor de Proteína beta-Amiloide , Camundongos Transgênicos , Placa Amiloide , Animais , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Camundongos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/genética , Modelos Animais de Doenças , Encéfalo/metabolismo , Encéfalo/patologia , Mutação , Envelhecimento/metabolismo , Envelhecimento/patologia , Conformação Proteica , Humanos
12.
Chem Biol Interact ; 395: 111012, 2024 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-38648920

RESUMO

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are associated with amyloid-ß (Aß) plaques and exhibit altered biochemical properties in human Alzheimer's disease (AD), as well as in the transgenic 5XFAD mouse model of AD amyloidosis. In the brains of the 5XFAD mouse model devoid of BChE enzyme (5XFAD/BChE-KO), incubation of tissue sections with exogenous BChE purified from human plasma (pl-BChE) leads to its association with Aß plaques and its biochemical properties are comparable to those reported for endogenous BChE associated with plaques in both human AD and in 5XFAD mouse brain tissue. We sought to determine whether these observations in 5XFAD/BChE-KO mice also apply to human brain tissues. To do so, endogenous ChE activity in human AD brain tissue sections was quenched with 50 % aqueous acetonitrile (MeCNaq) leaving the tissue suitable for further studies. Quenched sections were then incubated with recombinant AChE (r-AChE) or pl-BChE and stained for each enzymes' activity. Exogenous r-AChE or pl-BChE became associated with Aß plaques, and when bound, had properties that were comparable to the endogenous ChE enzymes associated with plaques in AD brain tissues without acetonitrile treatment. These findings in human AD brain tissue extend previous observations in the 5XFAD/BChE-KO mouse model and demonstrate that exogenously applied r-AChE and pl-BChE have high affinity for Aß plaques in human brain tissues. This association alters the biochemical properties of these enzymes, most likely due a conformational change. If incorporation of AChE and BChE in Aß plaques facilitates AD pathogenesis, blocking this association could lead to disease-modifying approaches to AD. This work provides a method to study the mechanism of AChE and BChE interaction with Aß plaque pathology in post-mortem human brain tissue.


Assuntos
Acetilcolinesterase , Doença de Alzheimer , Encéfalo , Butirilcolinesterase , Placa Amiloide , Humanos , Butirilcolinesterase/metabolismo , Butirilcolinesterase/química , Encéfalo/metabolismo , Encéfalo/patologia , Acetilcolinesterase/metabolismo , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Animais , Camundongos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Camundongos Transgênicos , Camundongos Knockout , Idoso , Proteínas Recombinantes/metabolismo , Masculino
13.
Alzheimers Dement ; 20(5): 3551-3566, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38624088

RESUMO

INTRODUCTION: Ozone (O3) is an air pollutant associated with Alzheimer's disease (AD) risk. The lung-brain axis is implicated in O3-associated glial and amyloid pathobiology; however, the role of disease-associated astrocytes (DAAs) in this process remains unknown. METHODS: The O3-induced astrocyte phenotype was characterized in 5xFAD mice by spatial transcriptomics and proteomics. Hmgb1fl/fl LysM-Cre+ mice were used to assess the role of peripheral myeloid cell high mobility group box 1 (HMGB1). RESULTS: O3 increased astrocyte and plaque numbers, impeded the astrocyte proteomic response to plaque deposition, augmented the DAA transcriptional fingerprint, increased astrocyte-microglia contact, and reduced bronchoalveolar lavage immune cell HMGB1 expression in 5xFAD mice. O3-exposed Hmgb1fl/fl LysM-Cre+ mice exhibited dysregulated DAA mRNA markers. DISCUSSION: Astrocytes and peripheral myeloid cells are critical lung-brain axis interactors. HMGB1 loss in peripheral myeloid cells regulates the O3-induced DAA phenotype. These findings demonstrate a mechanism and potential intervention target for air pollution-induced AD pathobiology. HIGHLIGHTS: Astrocytes are part of the lung-brain axis, regulating how air pollution affects plaque pathology. Ozone (O3) astrocyte effects are associated with increased plaques and modified by plaque localization. O3 uniquely disrupts the astrocyte transcriptomic and proteomic disease-associated astrocyte (DAA) phenotype in plaque associated astrocytes (PAA). O3 changes the PAA cell contact with microglia and cell-cell communication gene expression. Peripheral myeloid cell high mobility group box 1 regulates O3-induced transcriptomic changes in the DAA phenotype.


Assuntos
Doença de Alzheimer , Astrócitos , Proteína HMGB1 , Ozônio , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Proteína HMGB1/metabolismo , Camundongos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Camundongos Transgênicos , Modelos Animais de Doenças , Encéfalo/patologia , Encéfalo/metabolismo , Placa Amiloide/patologia , Placa Amiloide/metabolismo , Microglia/metabolismo , Poluentes Atmosféricos , Pulmão/patologia , Peptídeos beta-Amiloides/metabolismo
14.
J Alzheimers Dis ; 99(1): 121-143, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38640149

RESUMO

Background: Previous work from our group has shown that chronic exposure to Vanadium pentoxide (V2O5) causes cytoskeletal alterations suggesting that V2O5 can interact with cytoskeletal proteins through polymerization and tyrosine phosphatases inhibition, causing Alzheimer's disease (AD)-like hippocampal cell death. Objective: This work aims to characterize an innovative AD experimental model through chronic V2O5 inhalation, analyzing the spatial memory alterations and the presence of neurofibrillary tangles (NFTs), amyloid-ß (Aß) senile plaques, cerebral amyloid angiopathy, and dendritic spine loss in AD-related brain structures. Methods: 20 male Wistar rats were divided into control (deionized water) and experimental (0.02 M V2O5 1 h, 3/week for 6 months) groups (n = 10). The T-maze test was used to assess spatial memory once a month. After 6 months, histological alterations of the frontal and entorhinal cortices, CA1, subiculum, and amygdala were analyzed by performing Congo red, Bielschowsky, and Golgi impregnation. Results: Cognitive results in the T-maze showed memory impairment from the third month of V2O5 inhalation. We also noted NFTs, Aß plaque accumulation in the vascular endothelium and pyramidal neurons, dendritic spine, and neuronal loss in all the analyzed structures, CA1 being the most affected. Conclusions: This model characterizes neurodegenerative changes specific to AD. Our model is compatible with Braak AD stage IV, which represents a moment where it is feasible to propose therapies that have a positive impact on stopping neuronal damage.


Assuntos
Doença de Alzheimer , Modelos Animais de Doenças , Transtornos da Memória , Ratos Wistar , Compostos de Vanádio , Animais , Doença de Alzheimer/patologia , Doença de Alzheimer/induzido quimicamente , Masculino , Compostos de Vanádio/farmacologia , Ratos , Transtornos da Memória/patologia , Transtornos da Memória/induzido quimicamente , Aprendizagem em Labirinto/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Memória Espacial/efeitos dos fármacos , Emaranhados Neurofibrilares/patologia , Emaranhados Neurofibrilares/efeitos dos fármacos , Placa Amiloide/patologia , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/patologia , Administração por Inalação
15.
Int J Mol Sci ; 25(8)2024 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-38673909

RESUMO

Recruitment and accumulation of reactive astrocytes around senile plaques are common pathological features of Alzheimer's disease (AD), with unclear mechanisms. Chemerin, an adipokine implicated in neuroinflammation, acts through its receptor, chemokine-like receptor 1 (CMKLR1), which also functions as a receptor for amyloid ß (Aß). The impact of the chemerin/CMKLR1 axis on astrocyte migration towards Aß plaques is unknown. Here we investigated the effect of CMKLR1 on astrocyte migration around Aß deposition in APP/PS1 mice with Cmklr1 knockout (APP/PS1-Cmklr1-/-). CMKLR1-expressed astrocytes were upregulated in the cortices and hippocampi of 9-month-old APP/PS1 mice. Chemerin mainly co-localized with neurons, and its expression was reduced in the brains of APP/PS1 mice, compared to WT mice. CMKLR1 deficiency decreased astrocyte colocalization with Aß plaques in APP/PS1-Cmklr1-/- mice, compared to APP/PS1 mice. Activation of the chemerin/CMKLR1 axis promoted the migration of primary cultured astrocytes and U251 cells, and reduced astrocyte clustering induced by Aß42. Mechanistic studies revealed that chemerin/CMKLR1 activation induced STING phosphorylation. Deletion of STING attenuated the promotion of the chemerin/CMKLR1 axis relative to astrocyte migration and abolished the inhibitory effect of chemerin on Aß42-induced astrocyte clustering. These findings suggest the involvement of the chemerin/CMKLR1/STING pathway in the regulation of astrocyte migration and recruitment to Aß plaques/Aß42.


Assuntos
Doença de Alzheimer , Astrócitos , Quimiocinas , Peptídeos e Proteínas de Sinalização Intercelular , Placa Amiloide , Receptores de Quimiocinas , Animais , Astrócitos/metabolismo , Quimiocinas/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Camundongos , Receptores de Quimiocinas/metabolismo , Receptores de Quimiocinas/genética , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Humanos , Peptídeos beta-Amiloides/metabolismo , Camundongos Knockout , Movimento Celular , Transdução de Sinais , Camundongos Transgênicos , Camundongos Endogâmicos C57BL
16.
PLoS One ; 19(4): e0299534, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38574297

RESUMO

Alzheimer's disease (AD) is the most common neuronal disorder that leads to the development of dementia. Until nowadays, some therapies may alleviate the symptoms, but there is no pharmacological treatment. Microdosing lithium has been used to modify the pathological characteristics of the disease, with effects in both experimental and clinical conditions. The present work aimed to analyze the effects of this treatment on spatial memory, anxiety, and molecular mechanisms related to long-term memory formation during the aging process of a mouse model of accelerated aging (SAMP-8). Female SAMP-8 showed learning and memory impairments together with disruption of memory mechanisms, neuronal loss, and increased density of senile plaques compared to their natural control strain, the senescence-accelerated mouse resistant (SAMR-1). Chronic treatment with lithium promoted memory maintenance, reduction in anxiety, and maintenance of proteins related to memory formation and neuronal density. The density of senile plaques was also reduced. An increase in the density of gamma-aminobutyric acid A (GABAA) and α7 nicotinic cholinergic receptors was also observed and related to neuroprotection and anxiety reduction. In addition, this microdose of lithium inhibited the activation of glycogen synthase kinase-3beta (GSK-3ß), the classical mechanism of lithium cell effects, which could contribute to the preservation of the memory mechanism and reduction in senile plaque formation. This work shows that lithium effects in neuroprotection along the aging process are not related to a unique cellular mechanism but produce multiple effects that slowly protect the brain along the aging process.


Assuntos
Doença de Alzheimer , Lítio , Compostos de Fenilmercúrio , Camundongos , Feminino , Animais , Lítio/farmacologia , Lítio/uso terapêutico , Placa Amiloide/patologia , Glicogênio Sintase Quinase 3 beta , Doença de Alzheimer/patologia , Envelhecimento/metabolismo , Modelos Animais de Doenças
17.
Mol Brain ; 17(1): 21, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38685105

RESUMO

Dopamine plays important roles in cognitive function and inflammation and therefore is involved in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD). Drugs that increase or maintain dopamine levels in the brain could be a therapeutic strategy for AD. However, the effects of dopamine and its precursor levodopa (L-DOPA) on Aß/tau pathology in vivo and the underlying molecular mechanisms have not been studied in detail. Here, we investigated whether L-DOPA treatment alters neuroinflammation, Aß pathology, and tau phosphorylation in 5xFAD mice, a model of AD. We found that L-DOPA administration significantly reduced microgliosis and astrogliosis in 5xFAD mice. In addition, L-DOPA treatment significantly decreased Aß plaque number by upregulating NEP and ADAM17 levels in 5xFAD mice. However, L-DOPA-treated 5xFAD mice did not exhibit changes in tau hyperphosphorylation or tau kinase levels. These data suggest that L-DOPA alleviates neuroinflammatory responses and Aß pathology but not tau pathology in this mouse model of AD.


Assuntos
Proteína ADAM17 , Doença de Alzheimer , Peptídeos beta-Amiloides , Modelos Animais de Doenças , Levodopa , Camundongos Transgênicos , Doenças Neuroinflamatórias , Proteínas tau , Animais , Levodopa/farmacologia , Doença de Alzheimer/patologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Proteína ADAM17/metabolismo , Peptídeos beta-Amiloides/metabolismo , Proteínas tau/metabolismo , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/patologia , Doenças Neuroinflamatórias/metabolismo , Fosforilação/efeitos dos fármacos , Placa Amiloide/patologia , Placa Amiloide/metabolismo , Camundongos , Encéfalo/patologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo
18.
J Theor Biol ; 587: 111823, 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38608804

RESUMO

This paper introduces a new model to simulate the progression of senile plaques, focusing on scenarios where concentrations of amyloid beta (Aß) monomers and aggregates vary between neurons. Extracellular variations in these concentrations may arise due to limited diffusivity of Aß monomers and a high rate of Aß monomer production at lipid membranes, requiring a substantial concentration gradient for diffusion-driven transport of Aß monomers. The dimensionless formulation of the model is presented, which identifies four key dimensionless parameters governing the solutions for Aß monomer and aggregate concentrations, as well as the radius of a growing Aß plaque within the control volume. These parameters include the dimensionless diffusivity of Aß monomers, the dimensionless rate of Aß monomer production, and the dimensionless half-lives of Aß monomers and aggregates. A dimensionless parameter is then introduced to evaluate the validity of the lumped capacitance approximation. An approximate solution is derived for the scenario involving large diffusivity of Aß monomers and dysfunctional protein degradation machinery, resulting in infinitely long half-lives for Aß monomers and aggregates. In this scenario, the concentrations of Aß aggregates and the radius of the Aß plaque depend solely on a single dimensionless parameter that characterizes the rate of Aß monomer production. According to the approximate solution, the concentration of Aß aggregates is linearly dependent on the rate of monomer production, and the radius of an Aß plaque is directly proportional to the cube root of the rate of monomer production. However, when departing from the conditions of the approximate solution (e.g., finite half-lives), the concentrations of Aß monomers and aggregates, along with the plaque radius, exhibit complex dependencies on all four dimensionless parameters. For instance, under physiological half-life conditions, the plaque radius reaches a maximum value and stabilizes thereafter.


Assuntos
Peptídeos beta-Amiloides , Placa Amiloide , Peptídeos beta-Amiloides/metabolismo , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Humanos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Modelos Biológicos , Difusão
19.
J Mol Neurosci ; 74(2): 49, 2024 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-38668787

RESUMO

The pathogenesis of Alzheimer's disease (AD) is complex and involves an imbalance between production and clearance of amyloid-ß peptides (Aß), resulting in accumulation of Aß in senile plaques. Hypercholesterolemia is a major risk factor for developing AD, with cholesterol shown to accumulate in senile plaques and increase production of Aß. ABCG4 is a member of the ATP-binding cassette transporters predominantly expressed in the CNS and has been suggested to play a role in cholesterol and Aß efflux from the brain. In this study, we bred Abcg4 knockout (KO) with the APPSwe,Ind (J9) mouse model of AD to test the hypothesis that loss of Abcg4 would exacerbate the AD phenotype. Unexpectedly, no differences were observed in novel object recognition (NOR) and novel object placement (NOP) behavioral tests, or on histologic examinations of brain tissues for senile plaque numbers. Furthermore, clearance of radiolabeled Aß from the brains did not differ between Abcg4 KO and control mice. Metabolic testing by indirect calorimetry, glucose tolerance test (GTT), and insulin tolerance test (ITT) were also mostly similar between groups with only a few mild metabolic differences noted. Overall, these data suggest that the loss of ABCG4 did not exacerbate the AD phenotype.


Assuntos
Subfamília G de Transportadores de Cassetes de Ligação de ATP , Doença de Alzheimer , Animais , Masculino , Camundongos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Encéfalo/metabolismo , Encéfalo/patologia , Camundongos Endogâmicos C57BL , Placa Amiloide/patologia
20.
J Neuroimmunol ; 390: 578342, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38640827

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive decline that severely affects patients and their families. Genetic and environmental risk factors, such as viral infections, synergize to accelerate the aging-associated neurodegeneration. Genetic risk factors for late-onset AD (LOAD), which accounts for most AD cases, are predominantly implicated in microglial and immune cell functions. As such, microglia play a major role in formation of amyloid beta (Aß) plaques, the major pathological hallmark of AD. This review aims to provide an overview of the current knowledge regarding the role of microglia in Aß plaque formation, as well as their impact on morphological and functional diversity of Aß plaques. Based on this discussion, we seek to identify challenges and opportunities in this field with potential therapeutic implications.


Assuntos
Doença de Alzheimer , Microglia , Placa Amiloide , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/genética , Doença de Alzheimer/imunologia , Humanos , Placa Amiloide/patologia , Placa Amiloide/metabolismo , Microglia/metabolismo , Microglia/patologia , Animais , Peptídeos beta-Amiloides/metabolismo
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