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Abstract Background Alzheimer's disease (AD) was described in 1907, and since then it changed from a relatively rare condition to one of the most prevalent diseases. Objective To describe the evolution of the notions of dementias and AD, and to investigate the reasons for the increase in scientific interest in AD. Methods A historical analysis was carried out on knowledge about dementia, the site of mental activity, the relationships between brain diseases and mental activity, and on the advances in research about AD, since its discovery until the publication of the amyloid cascade hypothesis in 1992. A search was carried out in the National Library of Medicine (PubMed) for scientific articles that included the terms dementia or AD over 50 years, from 1972 to 2021. Results The scientific research on AD increased from 615 papers with the term AD in the first decade (1972-1981), to 100,028 papers in the last decade (2012-2021): an increase of 162.6 times whereas publications with the term dementia increased 28.6 times in the same period. In the 1960s and 1970s, a consensus was reached that AD is responsible for the majority of cases of dementia previously known as senile dementia. In the 1980s, beta-amyloid peptide was identified in the core of the senile plaque, hyperphosphorylated tau protein was found in neurofibrillary tangles, and a mutation was discovered in a hereditary form of AD. Conclusion The expansion of the concept of AD to include senile dementia, and the discoveries that occurred in the 1980s greatly expanded research in AD.
Resumo Antecedentes A doença de Alzheimer (DA) foi descrita em 1907 e, desde então, deixou de ser relativamente rara para se tornar uma das doenças mais prevalentes. Objetivo Descrever a evolução das noções sobre demências e DA e investigar as razões do aumento do interesse científico pela DA. Métodos Foi realizada uma análise histórica dos conhecimentos sobre demência, o local da atividade mental, as relações entre doenças cerebrais e a atividade mental, e sobre os avanços na pesquisa sobre a DA, desde a sua descoberta até a publicação da hipótese da cascata amiloide em 1992. Foi realizada uma busca na Biblioteca Nacional de Medicina dos Estados Unidos da América (PubMed) por artigos científicos que incluíssem os termos demência ou DA nos 50 anos, de 1972 a 2021. Resultados A pesquisa científica sobre DA aumentou de 615 artigos com o termo doença de Alzheimer na primeira década (1972-1981), para 100.028 artigos na última década (2012-2021): um aumento de 162,6 vezes enquanto as publicações com o termo demência aumentaram 28,6 vezes no mesmo período. Nas décadas de 1960 e 1970, chegou-se a um consenso de que a DA é responsável pela maioria dos casos de demência, anteriormente conhecida como demência senil. Na década de 1980, o peptídeo beta-amiloide foi identificado no núcleo da placa senil, a proteína tau hiperfosforilada foi encontrada em emaranhados neurofibrilares e uma mutação foi descoberta em uma forma hereditária de DA. Conclusão A expansão do conceito de DA para incluir a demência senil e as descobertas ocorridas na década de 1980 ampliaram enormemente a pesquisa em DA.
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Alzheimer′s disease (AD) is the most common neurodegenerative disease. Its etiology and pathogenesis remain unclear. Since its inception, the amyloid-β (Aβ) cascade hypothesis has dominated the field of AD research and has provided the intellectual framework for disease-modifying therapies. Nowadays, many Aβ-targeted therapies have been accelerated approval or received Food and Drug Administration′s breakthrough therapy designation which offers a new dawn for disease-modifying treating AD. This article reviews the research progress of clinical trials of Aβ-targeting modification therapies, and summarizes the lessons learned from the clinical failure with several classes of anti-Aβ drugs. Although many challenges remain, anti-Aβ therapies have become a promising treatment strategy for AD.
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Objectives:To analyze the potential biomarkers of behavioral and psychological symptoms of dementia (BPSD) in patients with Alzheimer′s disease (AD) continuum.Methods:A prospective cohort study was consecutively conducted on 179 patients with AD continuum (135 presented with BPSD, 44 patients without BPSD as control) from Capital Medical University, Beijing Tiantan Hospital, the Chinese imaging biomarkers and lifestyle cohort between January 1, 2021 and December 31, 2022. Gender, age, body max index, education level, diagnosis, the apolipoprotein E epsilon4 allele (APOE ε4) carrier status, the scores of the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA), cerebrospinal fluid (CSF) AD-related pathological biomarkers (Aβ 42, Aβ 40, Aβ 42/40, tTau, pTau181), and blood biomarkers (white blood cell count, red blood cell count, hemoglobin, platelet, total bilirubin, albumin, total cholesterol, triglyceride, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, fasting glucose, erythrocyte sedimentation rate, homocysteine, vitamin B 12, folate) were compared between the two groups by using hypothesis testing and univariate logistic regression analysis. Multivariate logistic regression analysis was used to analyze the potential biomarkers associated with BPSD in patients with AD. Results:Among the 179 patients with AD continuum in the final analysis, 77 patients were men, 102 cases were women; 35 patients were identified with mild cognitive impairment (MCI) due to AD and 144 patients with AD dementia stage, the mean age was (66.54±9.75) years. Compared with those in control group, patients with BPSD had lower cerebrospinal fluid (CSF) Aβ 40 and blood hemoglobin levels [7.08 (4.42, 15.42) vs 9.62 (6.45, 12.12) pg/L, (132.70±13.37) vs (138.80±14.38) g/L] ( U=-1.856, t=2.579, P<0.05). The levels of CSF Aβ 40 ( OR=0.030, 95% CI: 0.001-0.760) and blood hemoglobin ( OR=0.051, 95% CI: 0.004-0.670) were independently negatively associated with BPSD in patients with AD continuum (both P<0.05). Conclusion:The decreased levels of CSF Aβ 40 and blood hemoglobin could be considered as potential biomarkers in detecting BPSD in patients with AD continuum.
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The extracellular domain (p75ECD) of p75 neurotrophin receptor (p75NTR) antagonizes Aβ neurotoxicity and promotes Aβ clearance in Alzheimer's disease (AD). The impaired shedding of p75ECD is a key pathological process in AD, but its regulatory mechanism is largely unknown. This study was designed to investigate the presence and alterations of naturally-occurring autoantibodies against p75ECD (p75ECD-NAbs) in AD patients and their effects on AD pathology. We found that the cerebrospinal fluid (CSF) level of p75ECD-NAbs was increased in AD, and negatively associated with the CSF levels of p75ECD. Transgenic AD mice actively immunized with p75ECD showed a lower level of p75ECD and more severe AD pathology in the brain, as well as worse cognitive functions than the control groups, which were immunized with Re-p75ECD (the reverse sequence of p75ECD) and phosphate-buffered saline, respectively. These findings demonstrate the impact of p75ECD-NAbs on p75NTR/p75ECD imbalance, providing a novel insight into the role of autoimmunity and p75NTR in AD.
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Mice , Animals , Alzheimer Disease/pathology , Receptor, Nerve Growth Factor , Amyloid beta-Peptides , Autoantibodies , Mice, TransgenicABSTRACT
Alzheimer's disease (AD) and Parkinson's disease (PD) are the primary diseases in neurodegenerative diseases. Nowadays, AD is common in one of the ten individuals whose age is more than 65, and its prevalence is kept on increasing with aging. Very few treatments and no effective treatments are available for curing neurodegenerative diseases. Pathogenesis of neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, and their association with the nine hallmarks of aging were clearly described in this review. Instability in genomic, attrition in telomere, alterations in epigenetics, proteostasis loss, dysfunction in mitochondria, senescence in cells, sensing of deregulated nutrition, exhaustion of stem cells, and alterations in intercellular communication are the nine biological hallmarks of Aging. Improving the medical facilities for neurodegenerative diseases is very much essential. Doctors and researchers are doing surplus research to overcome the unavailability of proper treatments for such neurodegenerative diseases. Reason and the causes behind the diseases and their effects are explained in this review to enhance the further research to help the society.
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Abstract Alzheimer's disease is a neurodegenerative condition that causes changes in memory and cognition, in addition to behavioral disorders, and most commonly affects the elderly. Several studies in the literature have presented therapeutic measures in an attempt to interfere with the pathogenic mechanisms of the disease and to mitigate its clinical manifestations. Some factors, such as excitotoxicity, cholinergic dysfunctions, oxidative stress, tau protein hyperphosphorylation, changes in amyloid-beta peptide metabolism, herpes viruses, apolipoprotein E, glycogen synthase kinase 3, insulin resistance, and the endocannabinoid system seem to be related to pathophysiology of Alzheimer's disease. Given this, a literature review was carried out to address the molecular mechanisms associated with the pathophysiological hypotheses previously mentioned, aiming to better understanding their underlying causes and contributing to possible pharmacological strategies about treatment of the disease.
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Objective:To study the clinical effects of QingxinWendan decoction in the treatment of bipolar disorder (BD) manic episode.Methods:60 patients with BD manic episode treated in Hunan Brain Hospital from February 2020 to December 2020 were prospectively selected. They were included in the control group and the observation group according to the random alphabet method, with 30 cases in each group. The control group was treated with magnesium valproate sustained-release tablets, and the observation group was treated with Qingxin Wendan decoction combined with magnesium valproate sustained-release tablets. The curative effect was evaluated after 4 weeks of continuous treatment. The degree of mania before and after treatment was evaluated by Beck-Rafaelsen mania scale (BRMS); the cognitive function before and after treatment was evaluated by Wechsler Adult Intelligence Scale (WAIS-RC) and Wechsler Memory Scale (WMS); The levels of interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), neuron specific enolase (NSE) and amyloid β protein (Aβ) levels were measured by enzyme linked immunosorbent assay (ELISA) before and after treatment. Spearman correlation analysis was used to analyze the correlation between serum NSE and Aβ levels and WAIS-RC and WMS scores in the two groups.Results:The curative effect of the observation group was better than that of the control group, with statistically significant difference ( P<0.05). After treatment, the BRMS scores of the control group and the observation group decreased (all P<0.05), and the BRMS scores of the observation group were lower than those of the control group ( P<0.05); After treatment, the WAIS-RC and WMS scores of the control group and the observation group increased (all P<0.05), and the WAIS-RC and WMS scores of the observation group were higher than those of the control group (all P<0.05). After treatment, the serum levels of IL-1β, TNF-α, NSE and Aβ in two groups were decreased (all P<0.05), and the levels of IL-1β, TNF-α, NSE and Aβ in the observation group were lower than those in the control group (all P<0.05). NSE and Aβ levels were negatively correlated with WAIS-RC and WMS scores (all P<0.05). Conclusions:Magnesium valproate sustained-release tablets combined with Qingxin Wendan decoction in the treatment of patients with BD manic episode were superior to magnesium valproate sustained-release tablets alone in reducing manic score, IL-1β, TNF-α, NSE and Aβ levels, and improving the cognitive function of patients. The use of QingxinWendan decoction on top of valproate extended-release tablet treatment for BD manic episode was superior to treatment with valproate extended-release tablets alone in reducing mania scores, IL-1β, TNF-α, NSE and Aβ levels, as well as improving patients' cognitive function.
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Exosomes are nanoscal-scale vesicles containing a variety of proteins(HSP70, actin, Alix, etc.), lipids, mRNAs and miRNAs.They are commonly found in various tissues and cells of the organism.They are involved in processes such as intercellular communication, immune regulation and cell signaling pathway regulation, and then play an important role.Recent studies have shown that exosome-mediated intercellular signaling plays an important role in the progression of Alzheimer's disease(AD). This paper reviewed the general characteristics of exosomes, clarifies the possible role of exosomes in the pathogenesis of AD, and also discussed the application prospect and the related challenges of exosomes as a new potential option in the future treatment of AD.
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Alzheimer's disease (AD), the most common neurodegenerative disorder, is characterized by memory loss and cognitive dysfunction. The accumulation of misfolded protein aggregates including amyloid beta (Aβ) peptides and microtubule associated protein tau (MAPT/tau) in neuronal cells are hallmarks of AD. So far, the exact underlying mechanisms for the aetiologies of AD have not been fully understood and the effective treatment for AD is limited. Autophagy is an evolutionarily conserved cellular catabolic process by which damaged cellular organelles and protein aggregates are degraded via lysosomes. Recently, there is accumulating evidence linking the impairment of the autophagy-lysosomal pathway with AD pathogenesis. Interestingly, the enhancement of autophagy to remove protein aggregates has been proposed as a promising therapeutic strategy for AD. Here, we first summarize the recent genetic, pathological and experimental studies regarding the impairment of the autophagy-lysosomal pathway in AD. We then describe the interplay between the autophagy-lysosomal pathway and two pathological proteins, Aβ and MAPT/tau, in AD. Finally, we discuss potential therapeutic strategies and small molecules that target the autophagy-lysosomal pathway for AD treatment both in animal models and in clinical trials. Overall, this article highlights the pivotal functions of the autophagy-lysosomal pathway in AD pathogenesis and potential druggable targets in the autophagy-lysosomal pathway for AD treatment.
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Genetic variation in apolipoprotein E (APOE) influences Alzheimer's disease (AD) risk. APOE ε4 alleles are the strongest genetic risk factor for late onset sporadic AD. The AD risk is dose dependent, as those carrying one APOE ε4 allele have a 2-3-fold increased risk, while those carrying two ε4 alleles have a 10-15-fold increased risk. Individuals carrying APOE ε2 alleles have lower AD risk and those carrying APOE ε3 alleles have neutral risk. APOE is a lipoprotein which functions in lipid transport, metabolism, and inflammatory modulation. Isoform specific effects of APOE within the brain include alterations to Aβ, tau, neuroinflammation, and metabolism. Here we review the association of APOE with AD, the APOE isoform specific effects within brain and periphery, and potential therapeutics.
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Since the establishment of the biomarker-based A-T-N (Amyloid/Tau/Neurodegeneration) framework in Alzheimer's disease (AD), the diagnosis of AD has become more precise, and cerebrospinal fluid tests and positron emission tomography examinations based on this framework have become widely accepted. However, the A-T-N framework does not encompass the whole spectrum of AD pathologies, and problems with invasiveness and high cost limit the application of the above diagnostic methods aimed at the central nervous system. Therefore, we suggest the addition of an "X" to the A-T-N framework and a focus on peripheral biomarkers in the diagnosis of AD. In this review, we retrospectively describe the recent progress in biomarkers based on the A-T-N-X framework, analyze the problems, and present our perspectives on the diagnosis of AD.
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Alzheimer's disease (AD) is an age-related neurodegenerative disorder. Sever cognitive and memory impairments, huge increase in the prevalence of the disease, and lacking definite cure have absorbed worldwide efforts to develop therapeutic approaches. Since many drugs have failed in the clinical trials due to multifactorial nature of AD, symptomatic treatments are still in the center attention and now, nootropic medicinal plants have been found as versatile ameliorators to reverse memory disorders. In this work, anti-Alzheimer's activity of aqueous extract of areca nuts (Areca catechu L.) was investigated via in vitro and in vivo studies. It depicted good amyloid ß (Aß) aggregation inhibitory activity, 82% at 100 µg/mL. In addition, it inhibited beta-secretase 1 (BACE1) with IC50 value of 19.03 µg/mL. Evaluation of neuroprotectivity of the aqueous extract of the plant against H2O2-induced cell death in PC12 neurons revealed 84.5% protection at 1 µg/mL. It should be noted that according to our results obtained from Morris Water Maze (MWM) test, the extract reversed scopolamine-induced memory deficit in rats at concentrations of 1.5 and 3 mg/kg.
La enfermedad de Alzheimer (EA) es un trastorno neurodegenerativo relacionado con la edad. Los severos deterioros cognitivos y de la memoria, el enorme aumento de la prevalencia de la enfermedad y la falta de una cura definitiva han absorbido los esfuerzos mundiales para desarrollar enfoques terapéuticos. Dado que muchos fármacos han fallado en los ensayos clínicos debido a la naturaleza multifactorial de la EA, los tratamientos sintomáticos siguen siendo el centro de atención y ahora, las plantas medicinales nootrópicas se han encontrado como mejoradores versátiles para revertir los trastornos de la memoria. En este trabajo, se investigó la actividad anti-Alzheimer del extracto acuoso de nueces de areca (Areca catechu L.) mediante estudios in vitro e in vivo. Representaba una buena actividad inhibidora de la agregación de amiloide ß (Aß), 82% a 100 µg/mL. Además, inhibió la beta-secretasa 1 (BACE1) con un valor de CI50 de 19,03 µg/mL. La evaluación de la neuroprotección del extracto acuoso de la planta contra la muerte celular inducida por H2O2 en neuronas PC12 reveló una protección del 84,5% a 1 µg/mL. Cabe señalar que, de acuerdo con nuestros resultados obtenidos de la prueba Morris Water Maze (MWM), el extracto revirtió el déficit de memoria inducido por escopolamina en ratas a concentraciones de 1,5 y 3 mg/kg.
Subject(s)
Animals , Rats , Areca/chemistry , Plant Extracts/administration & dosage , Alzheimer Disease/drug therapy , beta-Amylase/antagonists & inhibitors , Amyloid beta-Peptides/drug effects , Aspartic Acid Endopeptidases/antagonists & inhibitors , Aspartic Acid Endopeptidases/drug effects , Neuroprotective Agents , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid Precursor Protein Secretases/drug effects , Alzheimer Disease/enzymology , Alzheimer Disease/prevention & control , Morris Water Maze Test , Medicine, TraditionalABSTRACT
RESUMO A doença neurodegenerativa mais comum no mundo é a doença de Alzheimer (DA), e 10% dos casos apresentam sintomas antes dos 65 anos, quase todos com associação genética, com hereditariedade autossômica dominante e penetrância entre 92 a 100% dos portadores. Na presente revisão, realizamos uma busca sobre as variantes genéticas associadas à doença de Alzheimer de início precoce (DAIP), enfatizando as características associadas mais importantes e as principais mutações já descritas. Os genes mais comumente relacionados com o surgimento da DAIP são APP, PSEN1, PSEN2 e MAPT, e mutações nestes afetam o metabolismo e a estrutura destas proteínas, resultando em acúmulos de peptídeo Aβ que causam inflamação e toxicidade no cérebro, levando à ativação da micróglia e promovendo a liberação de fatores neurotóxicos e pró-inflamatórios que aceleram a neurodegeneração. O gene PSEN1 é responsável por 70% das mutações conhecidas da DAIP, sendo a L166P associada à idade de ocorrência da doença abaixo dos 30 anos. Mutações em APP levam à agregação da proteína em placas neurodegenerativas. Todas as mutações descritas para MAPT estão associadas a um aumento dos emaranhados neurofibrilares. O polimorfismo E4 da Apolipoproteína E (APOE) influencia o aumento no risco de DAIP elevando as chances em três vezes para portadores heterozigotos e entre oito a dez vezes para os homozigotos. Apenas 5% das mutações associadas à DAIP são conhecidas, e novos estudos apresentam outros genes candidatos, bem como a importância de alterações epigenéticas na gênese desta doença.
SUMMARY The most common neurodegenerative disease in the world is Alzheimer's Disease (AD). Ten percent of Alzheimer patients experience symptoms before the age of 65, and almost all of them present genetic features of autosomal dominant inheritance nature, and penetrance of 92 to 100%. In the present review, we searched for genetic variants associated with early onset Alzheimer's disease (EOAD), emphasizing the most important characteristics and the main mutations. The genes most commonly related to the onset of EOAD are APP, PSEN1, PSEN2 and MAPT, whose mutations affect the metabolism and structure of these proteins. This process results in accumulations of Aβ peptide that leads to activation of the microglia and release of neurotoxic and pro-inflammatory factors that accelerate neurodegeneration. The PSEN1 gene is responsible for 70% of the known mutations in EOAD, while L166P is associated with below 30 years as the starting age of occurrence. APP mutations lead to protein aggregation in neurodegenerative plaques. All of the mutations described for MAPT are associated with an increase in neurofibrillary tangles. The E4 polymorphism of Apolipoprotein E (APOE) influences an increased risk of EOAD increasing up to three times the chances for heterozygous, and between eight and ten times for homozygotes carriers. Only 5% of the mutations associated with EOAD are known; new studies will show other candidate genes, as well as the importance of epigenetic factors changes in the etio-pathogenesis of this disease.
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Alzheimer′s disease (AD), the most common neurodegenerative disease, is a major challenge in China and all the world. However, the pathogenesis of AD remains unclear, and no disease-modifying therapies are available to prevent or treat the disease. Amyloid-beta (Aβ) and hyperphosphorylated tau protein are key pathological molecules of AD. A series of clinical trials targeting Aβ, tau protein and neuroinflammation have been carried out in the past 20 years, but none of them have been successful in attenuating the cognitive decline so far. This paper discusses the challenges of the current clinical trials of AD and proposes future directions for the research of AD prevention and treatment.
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Objective:To evaluate the role of hippocampal β-amyloid 42 (Aβ 42) deposition-induced accumulation of neutrophils in blood-brain barrier damage caused by sevoflurane anesthesia in aged rats. Methods:Seventy-two healthy male Wistar rats in which IT catheters were successfully planted, aged 18-20 months, weighing 600-650 g, were divided into 4 groups ( n=18 each) using a random number table method: control group (group C), γ-secretase inhibitor DAPT group (group D), sevoflurane anesthesia group (group S) and DAPT plus sevoflurane anesthesia group (group DS). Dimethyl sulfoxide 10 μl was intrathecally injected in group C and group S, and 30 min later group C inhaled 60% oxygen for 2 h, and group S inhaled 3.6% sevoflurane and 60% oxygen for 2 h and tibial fracture surgery was performed at the same time.DAPT 10 μl was intrathecally injected in group D and group DS, and 30 min later group D inhaled 60% oxygen for 2 h, and group DS inhaled 3.6% sevoflurane and 60% oxygen for 2 h and tibial fracture surgery was performed at the same time.The fear conditioning test was performed at 12 h after the end of treatment in each group, and the ratio of time spent freezing was calculated.The rats were sacrificed after the end of behavioral test, and hippocampal tissues were removed for determination of the expression of Aβ 42, occludin and matrix metalloproteinase-9 (MMP-9) (by Western blot), neutrophil count (by immuno-histochemistry), and content of Evans blue (EB) (by EB staining). Results:Compared with group C, the ratio of time spent freezing was significantly decreased, the expression of Aβ 42 and MMP-9 was up-regulated, the expression of occludin was down-regulated, the neutrophil count and content of EB were increased in group S and group DS ( P<0.05), and no significant change was found in the parameters mentioned above in group D ( P>0.05). Compared with group S, the ratio of time spent freezing was significantly increased, the expression of Aβ 42 and MMP-9 was down-regulated, the expression of occludin was up-regulated, the neutrophil count and content of EB were decreased in group DS ( P<0.05). Conclusion:The mechanism by which sevoflurane anesthesia leads to postoperative cognitive dysfunction is related to hippocampal Aβ 42 deposition-induced accumulation of neutrophils and causing damage to blood-brain barrier in aged rats.
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Age-related macular degeneration (AMD) is an age-related degenerative disease with complex pathogenesis, whose initial lesion is accompanied with immune inflammatory response. Amyloid beta (Aβ), a small-molecule protein generated by the hydrolysis of amyloid precursor protein, as the main component, is involved in the formation of drusen, which serves as the early characteristic of AMD. In the local inflammatory response of AMD, Aβ is an important pathological deposit, promoting the proliferation and differentiation of macrophages as well as changing their morphology to accelerate the progression of AMD. In addition, Aβ can also regulate immune molecules and the complement system by activating inflammatory pathways, thus mediating chronic retinal inflammation and promoting the course of AMD. However, since AMD is not caused by inflammation alone, only the immunosuppression may not be effective in inhibiting the course of AMD, and thus the future development is to rebalance the disordered immune system in AMD patients eyes.
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Blood-brain barrier (BBB) strictly controls matter exchange between blood and brain, and severely limits brain penetration of systemically administered drugs, resulting in ineffective drug therapy of brain diseases. However, during the onset and progression of brain diseases, BBB alterations evolve inevitably. In this review, we focus on nanoscale brain-targeting drug delivery strategies designed based on BBB evolutions and related applications in various brain diseases including Alzheimer's disease, Parkinson's disease, epilepsy, stroke, traumatic brain injury and brain tumor. The advances on optimization of small molecules for BBB crossing and non-systemic administration routes (
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Breast cancer brain metastases (BCBMs) are one of the most difficult malignancies to treat due to the intracranial location and multifocal growth. Chemotherapy and molecular targeted therapy are extremely ineffective for BCBMs due to the inept brain accumulation because of the formidable blood‒brain barrier (BBB). Accumulation studies prove that low density lipoprotein receptor-related protein 1 (LRP1) is promising target for BBB transcytosis. However, as the primary clearance receptor for amyloid beta and tissue plasminogen activator, LRP1 at abluminal side of BBB can clear LRP1-targeting therapeutics. Matrix metalloproteinase-1 (MMP1) is highly enriched in metastatic niche to promote growth of BCBMs. Herein, it is reported that nanoparticles (NPs-K-s-A) tethered with MMP1-sensitive fusion peptide containing HER2-targeting K and LRP1-targeting angiopep-2 (A), can surmount the BBB and escape LRP1-mediated clearance in metastatic niche. NPs-K-s-A revealed infinitely superior brain accumulation to angiopep-2-decorated NPs-A in BCBMs bearing mice, while comparable brain accumulation in normal mice. The delivered doxorubicin and lapatinib synergistically inhibit BCBMs growth and prolongs survival of mice bearing BCBMs. Due to the efficient BBB penetration, special and remarkable clearance escape, and facilitated therapeutic outcome, the fusion peptide-based drug delivery strategy may serve as a potential approach for clinical management of BCBMs.
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The hypotheses currently considered the most likely causes of Alzheimer's disease (AD) are amyloid beta peptide deposition in the cerebral cortex and hyperphosphorylation of the Tau protein, with the consequent formation of neurofibrillary tangles. In clinical practice, although not accurate, AD diagnosis is based on the exclusion of other diseases, behavioural assessments and complementary examinations, such as imaging and blood tests. Advances in the field of biotechnology have created exciting prospects for the early detection of AD via biomarker assessment, which is considered a safer and more efficient procedure. Molecules recognised as biomarkers can be expressed in some body fluids, including cerebrospinal fluid, saliva and blood. The presence of amyloid beta peptide and Tau can be confirmed in saliva, which is also an easily and non-invasively collectable material with an accessible cost. The objective was evaluate the concentrations of the t-Tau protein and Ab42 peptide in the saliva of elderly individuals with and without dementia of the AD type Method: The objective of this case-control study, involving a total of 120 individuals, was to analyse whether a correlation exists between variations in the concentrations of the t-Tau and Ab42 biomarkers in the saliva of patients with confirmed AD and individuals in the inclusion group but without AD . We found that t-Tau expression in AD patients is significantly lower than that in individuals without AD, whereas the salivary concentration of Ab42 is higher in patients with AD but not significantly different from that of the group without AD. Conclusion: Thus, we demonstrate the feasibility of using salivary biomarkers as predictive markers for diagnosis of Alzheimer's disease.
Las hipótesis consideradas actualmente como las causas más probables de la enfermedad de Alzheimer (EA) son la deposición de péptido beta amiloide en la corteza cerebral y la hiperfosforilación de la proteína Tau, con la consiguiente formación de ovillos neurofibrilares. En la práctica clínica, aunque no es precisa, el diagnóstico de la EA se basa en la exclusión de otras enfermedades, evaluaciones de comportamiento y exámenes complementarios, como imágenes y análisis de sangre. Los avances en el campo de la biotecnología han creado interesantes perspectivas para la detección temprana de la EA a través de la evaluación de biomarcadores, que se considera un procedimiento más seguro y más eficiente. Las moléculas reconocidas como biomarcadores se pueden expresar en algunos fluidos corporales, incluidos el líquido cerebroespinal, la saliva y la sangre. La presencia del péptido beta amiloide (AB) y la proteína Tau (t-Tau) se puede confirmar en la saliva, que también es un material fácil y no invasivo de recolección con un costo accesible. El objetivo fue evaluar las concentraciones de la proteína t-Tau y el péptido Ab42 en la saliva de las personas de edad avanzada con y sin demencia del tipo de tipo EA. El estudio de casos y controles, se realizó en un total de 120 personas, para analizar si existe una correlación entre las variaciones en las concentraciones de los biomarcadores t-Tau y Ab42 en la saliva de pacientes con EA confirmada e individuos en el grupo de inclusión pero sin AD. Encontramos que la expresión de t-Tau en pacientes con EA es significativamente menor que en individuos sin EA, mientras que la concentración salival de Ab42 es mayor en pacientes con EA pero no significativamente diferente de la del grupo sin la enfermedad . Por lo tanto, se demuestra la viabilidad del uso de biomarcadores salivales como marcadores predictivos para el diagnóstico de la enfermedad de Alzheimer.
Subject(s)
Humans , Male , Female , Middle Aged , Aged , Amyloid beta-Peptides/metabolism , tau Proteins/metabolism , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Saliva/metabolism , Saliva/chemistry , Biomarkers/analysis , Biomarkers/metabolism , Amyloid beta-Peptides/analysis , tau Proteins/analysisABSTRACT
To evaluate whether the polygenic profile modifies the development of sporadic Alzheimer's disease (sAD) and pathological biomarkers in cerebrospinal fluid (CSF), 462 sAD patients and 463 age-matched cognitively normal (CN) controls were genotyped for 35 single-nucleotide polymorphisms (SNPs) that are significantly associated with sAD. Then, the alleles found to be associated with sAD were used to build polygenic risk score (PRS) models to represent the genetic risk. Receiver operating characteristic (ROC) analyses and the Cox proportional hazards model were used to evaluate the predictive value of PRS for the sAD risk and age at onset. We measured the CSF levels of Aβ42, Aβ42/Aβ40, total tau (T-tau), and phosphorylated tau (P-tau) in a subgroup (60 sAD and 200 CN participants), and analyzed their relationships with the PRSs. We found that 14 SNPs, including SNPs in the APOE, BIN1, CD33, EPHA1, SORL1, and TOMM40 genes, were associated with sAD risk in our cohort. The PRS models built with these SNPs showed potential for discriminating sAD patients from CN controls, and were able to predict the incidence rate of sAD and age at onset. Furthermore, the PRSs were correlated with the CSF levels of Aβ42, Aβ42/Aβ40, T-tau, and P-tau. Our study suggests that PRS models hold promise for assessing the genetic risk and development of AD. As genetic risk profiles vary among populations, large-scale genome-wide sequencing studies are urgently needed to identify the genetic risk loci of sAD in Chinese populations to build accurate PRS models for clinical practice.