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1.
Alzheimers Res Ther ; 13(1): 150, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34488875

RESUMO

BACKGROUND: Aging is associated with declining protective immunity and persistent low-grade inflammatory responses, which significantly contribute to Alzheimer's disease (AD) pathogenesis. Detecting aging-related cerebral vulnerability associated with deterioration of the immune system requires from non-invasive biomarkers able to detect failures in the brain-immunity connection. Reduced levels of salivary lactoferrin (sLF), an iron-binding protein with immunomodulatory activity, have been related to AD diagnosis. However, it remains unknown whether decreased sLF is associated with increased cortical amyloid-beta (Aß) load and/or with loss of cortical integrity in normal aging. METHODS: Seventy-four cognitively normal older adults (51 females) participated in the study. We applied multiple linear regression analyses to assess (i) whether sLF is associated with cortical Aß load measured by 18F-Florbetaben (FBB)-positron emission tomography (PET), (ii) whether sLF-related variations in cortical thickness and cortical glucose metabolism depend on global Aß burden, and (iii) whether such sLF-related cortical abnormalities moderate the relationship between sLF and cognition. RESULTS: sLF was negatively associated with Aß load in parieto-temporal regions. Moreover, sLF was related to thickening of the middle temporal cortex, increased FDG uptake in the posterior cingulate cortex, and poorer memory. These associations were stronger in individuals showing the highest Aß burden. CONCLUSIONS: sLF levels are sensitive to variations in cortical Aß load, structural and metabolic cortical abnormalities, and subclinical memory impairment in asymptomatic older adults. These findings provide support for the use of sLF as a non-invasive biomarker of cerebral vulnerability in the general aging population.


Assuntos
Doença de Alzheimer , Lactoferrina , Idoso , Envelhecimento , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/metabolismo , Feminino , Humanos , Tomografia por Emissão de Pósitrons
2.
Inorg Chem ; 60(16): 12610-12620, 2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34351146

RESUMO

Herein, we report a new series of bifunctional chelators (BFCs) with a high affinity for amyloid aggregates, a strong binding affinity toward Cu(II), and favorable lipophilicity for potential blood-brain barrier penetration. The alkyl carboxylate ester pendant arms offer up to 3 orders of magnitude higher binding affinity toward Cu(II) and enable the BFCs to form stable 64Cu-radiolabeled complexes. Among the five compounds tested, the 64Cu-YW-7 and 64Cu-YW-10 complexes exhibit strong and specific staining of amyloid plaques in ex vivo autoradiography studies. Importantly, these BFCs have promising partition coefficient (log Doct) values of 0.91-1.26 and show some brain uptake in biodistribution studies using CD-1 mice. Overall, these BFCs could serve as lead compounds for the development of positron emission tomography imaging agents for AD diagnosis.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/metabolismo , Quelantes/química , Quelantes/metabolismo , Radioisótopos de Cobre , Interações Hidrofóbicas e Hidrofílicas , Tomografia por Emissão de Pósitrons , Doença de Alzheimer/metabolismo , Barreira Hematoencefálica/metabolismo
3.
Lancet Neurol ; 20(9): 739-752, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34418401

RESUMO

BACKGROUND: Plasma tau phosphorylated at threonine 217 (p-tau217) and plasma tau phosphorylated at threonine 181 (p-tau181) are associated with Alzheimer's disease tau pathology. We compared the diagnostic value of both biomarkers in cognitively unimpaired participants and patients with a clinical diagnosis of mild cognitive impairment, Alzheimer's disease syndromes, or frontotemporal lobar degeneration (FTLD) syndromes. METHODS: In this retrospective multicohort diagnostic performance study, we analysed plasma samples, obtained from patients aged 18-99 years old who had been diagnosed with Alzheimer's disease syndromes (Alzheimer's disease dementia, logopenic variant primary progressive aphasia, or posterior cortical atrophy), FTLD syndromes (corticobasal syndrome, progressive supranuclear palsy, behavioural variant frontotemporal dementia, non-fluent variant primary progressive aphasia, or semantic variant primary progressive aphasia), or mild cognitive impairment; the participants were from the University of California San Francisco (UCSF) Memory and Aging Center, San Francisco, CA, USA, and the Advancing Research and Treatment for Frontotemporal Lobar Degeneration Consortium (ARTFL; 17 sites in the USA and two in Canada). Participants from both cohorts were carefully characterised, including assessments of CSF p-tau181, amyloid-PET or tau-PET (or both), and clinical and cognitive evaluations. Plasma p-tau181 and p-tau217 were measured using electrochemiluminescence-based assays, which differed only in the biotinylated antibody epitope specificity. Receiver operating characteristic analyses were used to determine diagnostic accuracy of both plasma markers using clinical diagnosis, neuropathological findings, and amyloid-PET and tau-PET measures as gold standards. Difference between two area under the curve (AUC) analyses were tested with the Delong test. FINDINGS: Data were collected from 593 participants (443 from UCSF and 150 from ARTFL, mean age 64 years [SD 13], 294 [50%] women) between July 1 and Nov 30, 2020. Plasma p-tau217 and p-tau181 were correlated (r=0·90, p<0·0001). Both p-tau217 and p-tau181 concentrations were increased in people with Alzheimer's disease syndromes (n=75, mean age 65 years [SD 10]) relative to cognitively unimpaired controls (n=118, mean age 61 years [SD 18]; AUC=0·98 [95% CI 0·95-1·00] for p-tau217, AUC=0·97 [0·94-0·99] for p-tau181; pdiff=0·31) and in pathology-confirmed Alzheimer's disease (n=15, mean age 73 years [SD 12]) versus pathologically confirmed FTLD (n=68, mean age 67 years [SD 8]; AUC=0·96 [0·92-1·00] for p-tau217, AUC=0·91 [0·82-1·00] for p-tau181; pdiff=0·22). P-tau217 outperformed p-tau181 in differentiating patients with Alzheimer's disease syndromes (n=75) from those with FTLD syndromes (n=274, mean age 67 years [SD 9]; AUC=0·93 [0·91-0·96] for p-tau217, AUC=0·91 [0·88-0·94] for p-tau181; pdiff=0·01). P-tau217 was a stronger indicator of amyloid-PET positivity (n=146, AUC=0·91 [0·88-0·94]) than was p-tau181 (n=214, AUC=0·89 [0·86-0·93]; pdiff=0·049). Tau-PET binding in the temporal cortex was more strongly associated with p-tau217 than p-tau181 (r=0·80 vs r=0·72; pdiff<0·0001, n=230). INTERPRETATION: Both p-tau217 and p-tau181 had excellent diagnostic performance for differentiating patients with Alzheimer's disease syndromes from other neurodegenerative disorders. There was some evidence in favour of p-tau217 compared with p-tau181 for differential diagnosis of Alzheimer's disease syndromes versus FTLD syndromes, as an indication of amyloid-PET-positivity, and for stronger correlations with tau-PET signal. Pending replication in independent, diverse, and older cohorts, plasma p-tau217 and p-tau181 could be useful screening tools to identify individuals with underlying amyloid and Alzheimer's disease tau pathology. FUNDING: US National Institutes of Health, State of California Department of Health Services, Rainwater Charitable Foundation, Michael J Fox foundation, Association for Frontotemporal Degeneration, Alzheimer's Association.


Assuntos
Doença de Alzheimer/diagnóstico , Disfunção Cognitiva/diagnóstico , Degeneração Lobar Frontotemporal/diagnóstico , Proteínas tau/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/sangue , Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides/metabolismo , Biomarcadores/sangue , Disfunção Cognitiva/sangue , Disfunção Cognitiva/líquido cefalorraquidiano , Diagnóstico Diferencial , Feminino , Degeneração Lobar Frontotemporal/sangue , Degeneração Lobar Frontotemporal/líquido cefalorraquidiano , Humanos , Masculino , Pessoa de Meia-Idade , Fosforilação/fisiologia , Tomografia por Emissão de Pósitrons , Valor Preditivo dos Testes , Estudos Retrospectivos , Proteínas tau/sangue , Proteínas tau/líquido cefalorraquidiano
5.
Alzheimers Res Ther ; 13(1): 138, 2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34389066

RESUMO

BACKGROUND: Changes in grey matter covariance networks have been reported in preclinical and clinical stages of Alzheimer's disease (AD) and have been associated with amyloid-ß (Aß) deposition and cognitive decline. However, the role of tau pathology on grey matter networks remains unclear. Based on previously reported associations between tau pathology, synaptic density and brain structural measures, tau-related connectivity changes across different stages of AD might be expected. We aimed to assess the relationship between tau aggregation and grey matter network alterations across the AD continuum. METHODS: We included 533 individuals (178 Aß-negative cognitively unimpaired (CU) subjects, 105 Aß-positive CU subjects, 122 Aß-positive patients with mild cognitive impairment, and 128 patients with AD dementia) from the BioFINDER-2 study. Single-subject grey matter networks were extracted from T1-weighted images and graph theory properties including degree, clustering coefficient, path length, and small world topology were calculated. Associations between tau positron emission tomography (PET) values and global and regional network measures were examined using linear regression models adjusted for age, sex, and total intracranial volume. Finally, we tested whether the association of tau pathology with cognitive performance was mediated by grey matter network disruptions. RESULTS: Across the whole sample, we found that higher tau load in the temporal meta-ROI was associated with significant changes in degree, clustering, path length, and small world values (all p < 0.001), indicative of a less optimal network organisation. Already in CU Aß-positive individuals associations between tau burden and lower clustering and path length were observed, whereas in advanced disease stages elevated tau pathology was progressively associated with more brain network abnormalities. Moreover, the association between higher tau load and lower cognitive performance was only partly mediated (9.3 to 9.5%) through small world topology. CONCLUSIONS: Our data suggest a close relationship between grey matter network disruptions and tau pathology in individuals with abnormal amyloid. This might reflect a reduced communication between neighbouring brain areas and an altered ability to integrate information from distributed brain regions with tau pathology, indicative of a more random network topology across different AD stages.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Disfunção Cognitiva/diagnóstico por imagem , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/metabolismo , Humanos , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Proteínas tau/metabolismo
6.
Alzheimers Res Ther ; 13(1): 141, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34404456

RESUMO

BACKGROUND: To explore whether the combination of white matter hyperintensities (WMHs) and amyloid-beta (Aß) deposition is associated with worse cognitive performance on cognitive composites (CCs) domain scores in individuals with subjective cognitive decline (SCD). METHODS: Two hundred participants from the FACEHBI cohort underwent structural magnetic resonance imaging (MRI), 18F-florbetaben positron emission tomography (FBB-PET), and neuropsychological assessment. WMHs were addressed through the Fazekas scale, the Age-Related White Matter Changes (ARWMC) scale, and the FreeSurfer pipeline. Eight CCs domain scores were created using the principal component analysis (PCA). Age, sex, education, and apolipoprotein E (APOE) were used as adjusting variables. RESULTS: Adjusted multiple linear regression models showed that FreeSurfer (B - .245; 95% CI - .1.676, - .393, p = .016) and ß burden (SUVR) (B - .180; 95% CI - 2.140, - .292; p = .070) were associated with face-name associative memory CCs domain score, although the latest one was not statistically significant after correction for multiple testing (p = .070). There was non-significant interaction of these two factors on this same CCs domain score (p = .54). However, its cumulative effects on face-name associative performance indicated that those individuals with either higher WMH load or higher Aß burden showed the worst performance on the face-name associative memory CCs domain score. CONCLUSIONS: Our results suggest that increased WMH load and increased Aß are independently associated with poorer episodic memory performance in SCD individuals, indicating a cumulative effect of the combination of these two pathological conditions in promoting lower cognitive performance, an aspect that could help in terms of treatment and prevention.


Assuntos
Disfunção Cognitiva , Substância Branca , Peptídeos beta-Amiloides/metabolismo , Cognição , Disfunção Cognitiva/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Testes Neuropsicológicos , Substância Branca/diagnóstico por imagem
7.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360989

RESUMO

Increasing evidence suggests that elderly people with dementia are vulnerable to the development of severe coronavirus disease 2019 (COVID-19). In Alzheimer's disease (AD), the major form of dementia, ß-amyloid (Aß) levels in the blood are increased; however, the impact of elevated Aß levels on the progression of COVID-19 remains largely unknown. Here, our findings demonstrate that Aß1-42, but not Aß1-40, bound to various viral proteins with a preferentially high affinity for the spike protein S1 subunit (S1) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the viral receptor, angiotensin-converting enzyme 2 (ACE2). These bindings were mainly through the C-terminal residues of Aß1-42. Furthermore, Aß1-42 strengthened the binding of the S1 of SARS-CoV-2 to ACE2 and increased the viral entry and production of IL-6 in a SARS-CoV-2 pseudovirus infection model. Intriguingly, data from a surrogate mouse model with intravenous inoculation of Aß1-42 show that the clearance of Aß1-42 in the blood was dampened in the presence of the extracellular domain of the spike protein trimers of SARS-CoV-2, whose effects can be prevented by a novel anti-Aß antibody. In conclusion, these findings suggest that the binding of Aß1-42 to the S1 of SARS-CoV-2 and ACE2 may have a negative impact on the course and severity of SARS-CoV-2 infection. Further investigations are warranted to elucidate the underlying mechanisms and examine whether reducing the level of Aß1-42 in the blood is beneficial to the fight against COVID-19 and AD.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Fragmentos de Peptídeos/metabolismo , SARS-CoV-2/enzimologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Células A549 , Doença de Alzheimer/complicações , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/química , Animais , COVID-19/complicações , COVID-19/metabolismo , Chlorocebus aethiops , Humanos , Interleucina-6/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fragmentos de Peptídeos/química , Subunidades Proteicas/química , Subunidades Proteicas/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Células Vero , Internalização do Vírus
8.
Sci Transl Med ; 13(606)2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34380771

RESUMO

Point mutations in the amyloid precursor protein gene (APP) cause familial Alzheimer's disease (AD) by increasing generation or altering conformation of amyloid ß (Aß). Here, we describe the Uppsala APP mutation (Δ690-695), the first reported deletion causing autosomal dominant AD. Affected individuals have an age at symptom onset in their early forties and suffer from a rapidly progressing disease course. Symptoms and biomarkers are typical of AD, with the exception of normal cerebrospinal fluid (CSF) Aß42 and only slightly pathological amyloid-positron emission tomography signals. Mass spectrometry and Western blot analyses of patient CSF and media from experimental cell cultures indicate that the Uppsala APP mutation alters APP processing by increasing ß-secretase cleavage and affecting α-secretase cleavage. Furthermore, in vitro aggregation studies and analyses of patient brain tissue samples indicate that the longer form of mutated Aß, AßUpp1-42Δ19-24, accelerates the formation of fibrils with unique polymorphs and their deposition into amyloid plaques in the affected brain.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Doença de Alzheimer/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Encéfalo/metabolismo , Humanos
9.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360951

RESUMO

Epidemiological studies have implied that the nonsteroidal anti-inflammatory drug (NSAID) indomethacin slows the development and progression of Alzheimer's disease (AD). However, the underlying mechanisms are notably understudied. Using a chimeric mouse/human amyloid precursor protein (Mo/HuAPP695swe) and a mutant human presenilin 1 (PS1-dE9) (APP/PS1) expressing transgenic (Tg) mice and neuroblastoma (N) 2a cells as in vivo and in vitro models, we revealed the mechanisms of indomethacin in ameliorating the cognitive decline of AD. By screening AD-associated genes, we observed that a marked increase in the expression of α2-macroglobulin (A2M) was markedly induced after treatment with indomethacin. Mechanistically, upregulation of A2M was caused by the inhibition of cyclooxygenase-2 (COX-2) and lipocalin-type prostaglandin D synthase (L-PGDS), which are responsible for the synthesis of prostaglandin (PG)H2 and PGD2, respectively. The reduction in PGD2 levels induced by indomethacin alleviated the suppression of A2M expression through a PGD2 receptor 2 (CRTH2)-dependent mechanism. Highly activated A2M not only disrupted the production and aggregation of ß-amyloid protein (Aß) but also induced Aß efflux from the brain. More interestingly, indomethacin decreased the degradation of the A2M receptor, low-density lipoprotein receptor-related protein 1 (LRP1), which facilitated the brain efflux of Aß. Through the aforementioned mechanisms, indomethacin ameliorated cognitive decline in APP/PS1 Tg mice by decreasing Aß production and clearing Aß from the brains of AD mice.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Anti-Inflamatórios não Esteroides/farmacologia , Indometacina/farmacologia , Placa Amiloide/tratamento farmacológico , alfa-Macroglobulinas/metabolismo , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Linhagem Celular Tumoral , Ciclo-Oxigenase 2/metabolismo , Humanos , Indometacina/uso terapêutico , Oxirredutases Intramoleculares/metabolismo , Lipocalinas/metabolismo , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Placa Amiloide/metabolismo , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Regulação para Cima , alfa-Macroglobulinas/genética
10.
Alzheimers Res Ther ; 13(1): 144, 2021 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-34454596

RESUMO

BACKGROUND: Epidemiological studies link vascular disease risk factors such as atherosclerosis, hypertension, and diabetes mellitus with Alzheimer's disease (AD). Whether there are direct links between these conditions to ß-amyloid (Aß) aggregation and tau pathology is uncertain. METHODS: To investigate the possible link between atherosclerosis and AD pathology, we subjected triple transgenic (3 × Tg) AD mice to a high-fat diet (HFD) at 3 months of age, which corresponds to early adulthood in humans. RESULTS: After 9 months of treatment, HFD-treated 3 × Tg mice exhibited worse memory deficits accompanied by blood hypercoagulation, thrombocytosis, and chronic platelet activation. Procoagulant platelets from HFD-treated 3 × Tg mice actively induced the conversion of soluble Aß40 into fibrillar Aß aggregates, associated with increased expression of integrin αIIbß3 and clusterin. At 9 months and older, platelet-associated fibrillar Aß aggregates were observed to obstruct the cerebral blood vessels in HFD-treated 3 × Tg mice. HFD-treated 3 × Tg mice exhibited a greater cerebral amyloid angiopathy (CAA) burden and increased cerebral vascular permeability, as well as more extensive neuroinflammation, tau hyperphosphorylation, and neuron loss. Disaggregation of preexisting platelet micro-clots with humanized GPIIIa49-66 scFv Ab (A11) significantly reduced platelet-associated fibrillar Aß aggregates in vitro and improved vascular permeability in vivo. CONCLUSIONS: These findings suggest that a major contribution of atherosclerosis to AD pathology is via its effects on blood coagulation and the formation of platelet-mediated Aß aggregates that compromise cerebral blood flow and therefore neuronal function. This leads to cognitive decline.


Assuntos
Doença de Alzheimer , Aterosclerose , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Aterosclerose/genética , Encéfalo/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Ativação Plaquetária
11.
Nutrients ; 13(7)2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34371878

RESUMO

Alzheimer's disease (AD) is characterized by the aberrant processing of amyloid precursor protein (APP) and the accumulation of hyperphosphorylated tau, both of which are accompanied by neuroinflammation. Dietary supplementation with spray-dried porcine plasma (SDP) has anti-inflammatory effects in inflammation models. We investigated whether dietary supplementation with SDP prevents the neuropathological features of AD. The experiments were performed in 2- and 6-month-old SAMP8 mice fed a control diet, or a diet supplemented with 8% SDP, for 4 months. AD brain molecular markers were determined by Western blot and real-time PCR. Senescent mice showed reduced levels of p-GSK3ß (Ser9) and an increase in p-CDK5, p-tau (Ser396), sAPPß, and the concentration of Aß40, (all p < 0.05). SDP prevented these effects of aging and reduced Bace1 levels (all p < 0.05). Senescence increased the expression of Mme1 and Ide1 and pro-inflammatory cytokines (Il-17 and Il-18; all p < 0.05); these changes were prevented by SDP supplementation. Moreover, SDP increased Tgf-ß expression (p < 0.05). Furthermore, in aged mice, the gene expression levels of the microglial activation markers Trem2, Ym1, and Arg1 were increased, and SDP prevented these increases (all p < 0.05). Thus, dietary SDP might delay AD onset by reducing its hallmarks in senescent mice.


Assuntos
Doença de Alzheimer/prevenção & controle , Encéfalo/efeitos dos fármacos , Suplementos Nutricionais , Plasma , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Ração Animal , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Quinase 5 Dependente de Ciclina/metabolismo , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/metabolismo , Mediadores da Inflamação/metabolismo , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Emaranhados Neurofibrilares/efeitos dos fármacos , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Fragmentos de Peptídeos/metabolismo , Fosforilação , Transdução de Sinais , Secagem por Atomização , Sus scrofa , Proteínas tau/metabolismo
12.
Nutrients ; 13(7)2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34371921

RESUMO

The study of different natural products can provide a wealth of bioactive compounds, and more interestingly, their combination can exert a new strategy for several neurodegenerative diseases with major public health importance, such as Alzheimer's disease (AD). Here, we investigated the synergistic neuroprotective effects of a mixed extract composed of docosahexaenoic acid, Ginkgo biloba, D-pinitol, and ursolic acid in several transgenic Caenorhabditis elegans (C. elegans) and a senescence-accelerated prone mice 8 (SAMP8) model. First, we found a significantly higher survival percentage in the C. elegans group treated with the natural product mixture compared to the single extract-treated groups. Likewise, we found a significantly increased lifespan in group of C. elegans treated with the natural product mixture compared to the other groups, suggesting synergistic effects. Remarkably, we determined a significant reduction in Aß plaque accumulation in the group of C. elegans treated with the natural product mixture compared to the other groups, confirming synergy. Finally, we demonstrated better cognitive performance in the group treated with the natural product mixture in both AD models (neuronal Aß C. elegans strain CL2355 and the SAMP8 mice model), confirming the molecular results and unraveling the synergist effects of this combination. Therefore, our results proved the potential of this new natural product mixture for AD therapeutic strategies.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Produtos Biológicos/farmacologia , Encéfalo/efeitos dos fármacos , Cognição/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/metabolismo , Animais , Animais Geneticamente Modificados , Encéfalo/metabolismo , Encéfalo/patologia , Caenorhabditis elegans/genética , Modelos Animais de Doenças , Longevidade , Camundongos , Neurônios/metabolismo , Neurônios/patologia , Estresse Oxidativo/efeitos dos fármacos , Placa Amiloide
13.
Adv Clin Chem ; 103: 135-190, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34229849

RESUMO

Amyloid plaques generated from the accumulation of amyloid-ß peptides (Aß) fibrils in the brain is one of the main hallmarks of Alzheimer's disease (AD), a most common neurodegenerative disorder. Aß aggregation can produce neurotoxic oligomers and fibrils, which has been widely accepted as the causative factor in AD pathogenesis. Accordingly, both soluble oligomers and insoluble fibrils have been considered as diagnostic biomarkers for AD. Among the existing analytical methods, fluorometry using fluorescent probes has exhibited promising potential in quantitative detection and imaging of both soluble and insoluble Aß species, providing a valuable approach for the diagnosis and drug development of AD. In this review, the most recent advances in the fluorescent probes for soluble or insoluble Aß aggregates are discussed in terms of design strategy, probing mechanism, and potential applications. In the end, future research directions of fluorescent probes for Aß species are also proposed.


Assuntos
Doença de Alzheimer/diagnóstico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Corantes Fluorescentes/química , Encéfalo/metabolismo , Humanos , Estrutura Molecular
14.
Med Hypotheses ; 154: 110645, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34315048

RESUMO

Alzheimer's disease (AD) is a progressive incurable neurodegenerative disease of the brain afflicting a third of the population aged 85 and older. Pathologic hallmarks include extracellular plaques of amyloid-beta (Aß), intraneuronal neurofibrillary tangles of hyperphosphorylated tau protein, synaptic destruction, neuronal death, and brain atrophy. Neuroinflammation, mediated by microglia, is a central component of the disease, and is intricately connected with peripheral inflammation. The clinical manifestations include progressive memory loss and eventual death. The present treatment of AD is largely ineffective. Nearly all AD is late-onset and presents age 65 or older, and the most common genetic risk factor is carriage of an apolipoprotein (APO) E4 allele, seen in about 25% of the general population. Individuals carrying an APOE4 allele produce more Aß and clear it less efficiently from the brain throughout life. There has been accumulating pathologic and clinical evidence that microbes, particularly the herpes simplex virus (HSV), is a causative factor for AD, most notable in carriers of the APOE4 allele. Eighty percent of the adult population harbors HSV and it resides in the trigeminal ganglion in latent state throughout life, but periodically reactivates, traveling antegrade resulting in herpes labialis and traveling retrograde into the brain leading to neuroinflammation. Functioning as an antimicrobial peptide, Aß inactivates HSV and the recurring process culminates in a buildup of Aß plaque and other hallmarks of AD over time. Periodontal disease exists in 20-50% of the adult population and is also a causative factor for AD. Accordingly, bacteria causing periodontal disease and their byproducts can enter the brain directly via the trigeminal nerve or indirectly through the bloodstream, resulting in AD pathology over time. There are many other promoters of AD, particularly inflammatory conditions outside of the brain, that can be mitigated. Small trials are finally in progress testing antimicrobial drugs for the prevention and treatment of AD. In the meantime, a more proactive approach to the prevention and treatment of AD is posited, with an emphasis on prevention, since the pathologic underpinnings of the disease start decades before the clinical manifestations. Individuals can be stratified in risk categories using family history, periodontal disease presence, APOE4 carriage, and HSV IgG positivity. Moderate- and high-risk individuals can be treated safely with various preventive measures and appropriate antimicrobial agents as discussed. Importantly, the proposed treatments are concordant with the accepted practice of medicine, and if utilized, could significantly decrease AD prevalence.


Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Idoso , Doença de Alzheimer/terapia , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Humanos , Emaranhados Neurofibrilares/metabolismo , Placa Amiloide
15.
ACS Chem Neurosci ; 12(15): 2940-2945, 2021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34292705

RESUMO

Hemes have been suggested to play a central role in Alzheimer's disease since they show high peroxidase reactivity when bound to amyloid ß peptides, leading to the production of reactive oxygen species. Here we used Fourier transform infrared and Raman imaging on Alzheimer's diseased mice and human brain tissue. Our finding suggests the accumulation of hemes in the senile plaques of both murine and human samples. We compared the Raman signature of the plaques to the ones of various hemeoproteins and to the hemin-Aß-42 complex. The detected Raman signature of the plaques does not allow identifying the type of heme accumulating in the plaques.


Assuntos
Doença de Alzheimer , Placa Amiloide , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Humanos , Camundongos , Camundongos Transgênicos
16.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 52(4): 605-611, 2021 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-34323038

RESUMO

Objective: To construct a nanodelivery system surface-modified with RD2 peptide (polypeptide sequence PTLHTHNRRRRR) for brain tissue penetration and ß-amyloid (Aß) binding. Epigallocatechin-3-gallate (EGCG) was selected for encapsulation in the targeted delivery system and its therapeutic potential for Alzheimer's disease (AD) was investigated. Methods: EGCG-load nanoparticles (NP/EGCG), NP/EGCG with RD2 peptide surface modification (RD2-NP/EGCG), as well as RD2 peptide-modified blank nanoparticles (RD2-NP) were prepared and characterized. Thioflavin T assay was done to assess the ability of RD2-NP to bind with Aß and ex vivo imaging was conducted to evaluate the distribution of RD2-NP in brain lesion sites. The AD mice model was established by injecting oligomeric Aß 42 in the bilateral hippocampi of ICR mice. Then AD mice were administered intravenously through the tail vein with normal saline, EGCG solution, NP/EGCG or RD2-NP/EGCG for 28 d, respectively, and the Morris water maze tests were performed to assess the spatial memory of mice. Subsequently, RT-PCR method was used to determine the mRNA levels of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) in the hippocampus of the mice, and the morphological changes of hippocampal neurons were observed with Nissl staining. Additionally, the pathological changes of heart, liver, spleen, lung, and kidney were characterized by hematoxylin-eosin (HE) staining. Results: The particle diameter of the prepared RD2-NP/EGCG was (204.83±2.80) nm and the zeta potential was -23.88 mV. The encapsulation efficiency and drug loading capacity were 94.39% and 5.90%, respectively. The RD2 peptide modification has no significant effect on the physiochemical properties of the nanoparticles. RD2-NP had good Aß binding ability, and it could be concentrated in hippocampus and cerebral cortex, the most common Aß deposition sites. The four-week RD2-NP/EGCG treatment significantly decreased the expression of the pro-inflammatory cytokine TNF-α and IL-1ß, restored neuronal losses and hippocampal damage, and ameliorated spatial memory impairment in AD model mice. Moreover, treatment with the RD2-NP/EGCG did not present organ toxicity. Conclusion: Surface modified RD2 peptide nanodelivery system can efficiently deliver drugs to AD lesions and improve the therapeutic effect of EGCG on AD.


Assuntos
Doença de Alzheimer , Nanopartículas , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/metabolismo , Catequina/análogos & derivados , Modelos Animais de Doenças , Hipocampo , Camundongos , Camundongos Endogâmicos ICR , Oligopeptídeos
17.
Nat Commun ; 12(1): 4304, 2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-34262030

RESUMO

Plasma tau phosphorylated at threonine 181 (p-tau181) predicts Alzheimer's disease (AD) pathology with high accuracy in the general population. In this study, we investigated plasma p-tau181 as a biomarker of AD in individuals with Down syndrome (DS). We included 366 adults with DS (240 asymptomatic, 43 prodromal AD, 83 AD dementia) and 44 euploid cognitively normal controls. We measured plasma p-tau181 with a Single molecule array (Simoa) assay. We examined the diagnostic performance of p-tau181 for the detection of AD and the relationship with other fluid and imaging biomarkers. Plasma p-tau181 concentration showed an area under the curve of 0.80 [95% CI 0.73-0.87] and 0.92 [95% CI 0.89-0.95] for the discrimination between asymptomatic individuals versus those in the prodromal and dementia groups, respectively. Plasma p-tau181 correlated with atrophy and hypometabolism in temporoparietal regions. Our findings indicate that plasma p-tau181 concentration can be useful to detect AD in DS.


Assuntos
Doença de Alzheimer/diagnóstico , Síndrome de Down/diagnóstico , Proteínas tau/sangue , Adulto , Doença de Alzheimer/sangue , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Área Sob a Curva , Atrofia , Biomarcadores/sangue , Biomarcadores/metabolismo , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Cognição , Estudos Transversais , Progressão da Doença , Síndrome de Down/sangue , Síndrome de Down/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neurofilamentos/sangue , Fosforilação , Proteínas tau/metabolismo
18.
Int J Mol Sci ; 22(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209586

RESUMO

Amyloid beta (Aß)-induced abnormal neuroinflammation is recognized as a major pathological feature of Alzheimer's disease (AD), which results in memory impairment. Research exploring low-grade systemic inflammation and its impact on the development and progression of neurodegenerative disease has increased. A particular research focus has been whether systemic inflammation arises only as a secondary effect of disease, or it is also a cause of pathology. The inflammasomes, and more specifically the NLRP3 inflammasome, are crucial components of the innate immune system and are usually activated in response to infection or tissue damage. Although inflammasome activation plays critical roles against various pathogens in host defense, overactivation of inflammasome contributes to the pathogenesis of inflammatory diseases, including acute central nervous system (CNS) injuries and chronic neurodegenerative diseases, such as AD. This review summarizes the current literature on the role of the NLRP3 inflammasome in the pathogenesis of AD, and its involvement in infections, particularly SARS-CoV-2. NLRP3 might represent the crossroad between the hypothesized neurodegeneration and the primary COVID-19 infection.


Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Doença de Alzheimer/metabolismo , Animais , Coronavirus/patogenicidade , Humanos , Imunidade Inata , Microglia/metabolismo , Viroses/imunologia , Viroses/patologia
19.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209113

RESUMO

Understanding the physiopathology of Alzheimer's disease (AD) has improved substantially based on studies of mouse models mimicking at least one aspect of the disease. Many transgenic lines have been established, leading to amyloidosis but lacking neurodegeneration. The aim of the current study was to generate a novel mouse model that develops neuritic plaques containing the aggressive pyroglutamate modified amyloid-ß (pEAß) species in the brain. The TAPS line was developed by intercrossing of the pEAß-producing TBA2.1 mice with the plaque-developing line APPswe/PS1ΔE9. The phenotype of the new mouse line was characterized using immunostaining, and different cognitive and general behavioral tests. In comparison to the parental lines, TAPS animals developed an earlier onset of pathology and increased plaque load, including striatal pEAß-positive neuritic plaques, and enhanced neuroinflammation. In addition to abnormalities in general behavior, locomotion, and exploratory behavior, TAPS mice displayed cognitive deficits in a variety of tests that were most pronounced in the fear conditioning paradigm and in spatial learning in comparison to the parental lines. In conclusion, the combination of a pEAß- and a plaque-developing mouse model led to an accelerated amyloid pathology and cognitive decline in TAPS mice, qualifying this line as a novel amyloidosis model for future studies.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Disfunção Cognitiva/metabolismo , Doença de Alzheimer/patologia , Animais , Linhagem Celular , Disfunção Cognitiva/patologia , Modelos Animais de Doenças , Camundongos
20.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209175

RESUMO

Apolipoprotein E (ApoE) isoforms exert intricate effects on cellular physiology beyond lipid transport and metabolism. ApoEs influence the onset of Alzheimer's disease (AD) in an isoform-dependent manner: ApoE4 increases AD risk, while ApoE2 decreases it. Previously we demonstrated that syndecans, a transmembrane proteoglycan family with increased expression in AD, trigger the aggregation and modulate the cellular uptake of amyloid beta (Aß). Utilizing our previously established syndecan-overexpressing cellular assays, we now explore how the interplay of ApoEs with syndecans contributes to key events, namely uptake and aggregation, in Aß pathology. The interaction of ApoEs with syndecans indicates isoform-specific characteristics arising beyond the frequently studied ApoE-heparan sulfate interactions. Syndecans, and among them the neuronal syndecan-3, increased the cellular uptake of ApoEs, especially ApoE2 and ApoE3, while ApoEs exerted opposing effects on syndecan-3-mediated Aß uptake and aggregation. ApoE2 increased the cellular internalization of monomeric Aß, hence preventing its extracellular aggregation, while ApoE4 decreased it, thus helping the buildup of extracellular plaques. The contrary effects of ApoE2 and ApoE4 remained once Aß aggregated: while ApoE2 reduced the uptake of Aß aggregates, ApoE4 facilitated it. Fibrillation studies also revealed ApoE4's tendency to form fibrillar aggregates. Our results uncover yet unknown details of ApoE cellular biology and deepen our molecular understanding of the ApoE-dependent mechanism of Aß pathology.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Apolipoproteína E2/metabolismo , Apolipoproteína E4/metabolismo , Apolipoproteínas E/metabolismo , Agregados Proteicos , Sindecana-3/metabolismo , Linhagem Celular Tumoral , Humanos , Isoformas de Proteínas
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