Suchergebnisse

Fengjin Zhang,1,2 Linlan Jiang11Department of Pharmacy, General Hospital of Guangzhou Military Command, Guangzhou City, People's Republic of China; 2School of Bioscience and Bioengineering, South China University of Technology, Guangzhou City, People's Republic of ChinaAbstract: Amyloid-β plaques and neurofibrillary tangles are the main neuropathological hallmarks in Alzheimer's disease (AD), the most common cause of dementia in the elderly. However, it has become increasingly apparent that neuroinflammation plays a significant role in the pathophysiology of AD. This review summarizes the current status of neuroinflammation research related to AD, focusing on the connections between neuroinflammation and some inflammation factors in AD. Among these connections, we discuss the dysfunctional blood–brain barrier and alterations in the functional responses of microglia and astrocytes in this process. In addition, we summarize and discuss the role of intracellular signaling pathways involved in inflammatory responses in astrocytes and microglia, including the mitogen-activated protein kinase pathways, nuclear factor-kappa B cascade, and peroxisome proliferator–activated receptor-gamma transcription factors. Finally, the dysregulation of the control and release of pro- and anti-inflammatory cytokines and classic AD pathology (amyloid plaques and neurofibrillary tangles) in AD is also reviewed.Keywords: inflammation, blood–brain barrier, glial cells, intracellular signaling pathways, inflammatory factors

Understanding amyloid beta and Alzheimer's disease: the key to helping AD patients
Efforts to prevent or treat Alzheimer's Disease (AD) by targeting Amyloid beta (Aβ) assemblies should be continued, but the strategies should be altered dramatically. The most common error with the treatment of Alzheimer's Disease (AD) has been to confuse effects with causes. AD begins with small Amyloid beta (Aβ) assemblies, oligomers, that damage synaptic and organelle membranes. Pathogenic oligomers should be suppressed long before symptoms appear. The root causes of Alzheimer's Disease (AD) are poorly understood and often misunderstood. Yes, everyone knows about plaques and tangles that contain amyloid beta (Aβ) and tau fibrils; these have been observed in the brains of most Alzheimer's patients since the 19th century. Billions have been spent to develop treatments that target these assemblies with almost no success. Just as war cannot be prevented by analyzing battlefield carnage, AD treatments based on analyses of plaques and tangles have failed. By the time they appear, it may be too late to avoid damage or halt the progression of AD.

Alzheimer's disease (AD) is a chronic neurodegenerative disease leading to cognitive decline, dementia, and ultimately death. Despite extensive R&D efforts, there are no diseases modifying treatments for AD available. The stage in which patients receive a clinical diagnosis of probable AD may be too late for disease modifying pharmacotherapy. Prevention strategies may be required to successfully tackle AD. Preclinical AD applies to over half of all healthy elderly subjects and manifests by signs of amyloid deposition and/or neuronal injury in the brain, preceding the stage in which symptoms of dementia, cognitive and functional impairment become observable. Prevention trials in preclinical AD require longer and larger clinical trials using biomarkers and cognitive endpoints, which requires collaboration across academia, government and industry.

Indonesia is the fourth most populous country in the world. An increase number in the proportion of elders is accompanied by an increase of degenerative diseases and disabilities, including Alzheimer's disease (AD). Prevalence of dementia in Indonesia is 1.2 million cases in 2015 and will keep increasing up to 3,980,000 in 2050. This study discusses data on the prevalence of dementia's risk factors in Indonesia, calculates population-attributable risks (PAR) to identify the number of dementia cases that could be prevented, and determines which intervention strategies will have the most significant effect in reducing Alzheimer's Disease (AD) cases. Prevalence of potentially modifiable risk factors for AD such as low education, hypertension, diabetes, obesity, and mental disorders are still high. Moreover, the prevalences keep increasing for the last five years. Low education has the highest estimated PAR, which could significantly lower new AD cases if it is being improved. Ten and thirty percent of risk factor reduction can decrease AD cases by 18,000 and 66,000 cases. In addition, reducing physical inactivity by 10% and 30% can reduce 19,000 and 55,000 cases of AD respectively; lowering 10% prevalence of midlife hypertension and diabetes can reduce 2400 and 1600 cases of AD. Decreasing 10% of all risk factors is estimated to reduce 22,000 of new AD cases. By reducing these modifiable risk factors, especially by improving access to education, the incidence of AD could be greatly reduced. This review is expected to give suggestion to the government in determining the priority scale of controlling risk factors for reducing the social and economic burden caused by AD.

PUBLIC HEALTH IMPORTANCE AND PREVENTION In the past century, life expectancy has increased more than 27 years. As the number of elderly persons has dramatically increased, Alzheimer's disease (AD) has become one of the major public health problems in the United States and the entire developed world. The "prevalence and malignancy of AD," as described in a two-page editorial written in 1976 by Dr. Robert Katzman (1), has become well known to physicians as well as the lay public. In the editorial, Katzman estimated the prevalence and mortality due to AD, and placed AD as a leading cause of death in the United States. Hebert has shown that the impact of AD will be ever more dramatic over the next 50 years as the numbers of very elderly in the population rise at an accelerated rate (2). Projecting age-specific prevalence data for AD to the population distributions obtained from the U.S. Census Bureau, there were 4.5 million cases of AD in the United States in the year 2000 and there will be 13.2 million in the year 2050.

Procedures of data collection on hospitalizations for Alzheimer's disease are compared among the countries of the European Union. Data were obtained from the national institutes of statistics and ministries of health. Information relates to the type of health institutions collecting data in a systematic way, procedures of codification and publication, collection of associated diagnoses, and characteristics of the patient. Coverage and coding practices differ markedly between countries. Where possible, levels of hospitalization rates for Alzheimer's disease (AD) are assessed. Hospitalization rates for AD increase significantly with age and do not differ much between males and females. Codification of diagnoses according to ICD-10 leads to a much lower level of hospitalization rates than following ICD-9. Data on outpatients and from private hospitals are presently not available and should be collected by the health system.

Procedures of data collection on hospitalizations for Alzheimer's disease are compared among the countries of the European Union. Data were obtained from the national institutes of statistics and ministries of health. Information relates to the type of health institutions collecting data in a systematic way, procedures of codification and publication, collection of associated diagnoses, and characteristics of the patient. Coverage and coding practices differ markedly between countries. Where possible, levels of hospitalization rates for Alzheimer's disease (AD) are assessed. Hospitalization rates for AD increase significantly with age and do not differ much between males and females. Codification of diagnoses according to ICD-10 leads to a much lower level of hospitalization rates than following ICD-9. Data on outpatients and from private hospitals are presently not available and should be collected by the health system.

This is the final version of the article. Available from the publisher via the DOI in this record. ; Although mitochondrial dysfunction is a consistent feature of Alzheimer's disease in the brain and blood, the molecular mechanisms behind these phenomena are unknown. Here we have replicated our previous findings demonstrating reduced expression of nuclear-encoded oxidative phosphorylation (OXPHOS) subunits and subunits required for the translation of mitochondrial-encoded OXPHOS genes in blood from people with Alzheimer's disease and mild cognitive impairment. Interestingly this was accompanied by increased expression of some mitochondrial-encoded OXPHOS genes, namely those residing closest to the transcription start site of the polycistronic heavy chain mitochondrial transcript (MT-ND1, MT-ND2, MT-ATP6, MT-CO1, MT-CO2, MT-C03) and MT-ND6 transcribed from the light chain. Further we show that mitochondrial DNA copy number was unchanged suggesting no change in steady-state numbers of mitochondria. We suggest that an imbalance in nuclear and mitochondrial genome-encoded OXPHOS transcripts may drive a negative feedback loop reducing mitochondrial translation and compromising OXPHOS efficiency, which is likely to generate damaging reactive oxygen species. ; This work represents independent research part funded by the InnoMed (Innovative Medicines in Europe) an Integrated Project funded by the European Union of the Sixth Framework program priority FP6-2004-LIFESCIHEALTH-5, Alzheimer's Research UK, The John and Lucille van Geest Foundation, the Rosetrees Trust, the National Institute for Health Research (NIHR) Biomedical Research Centre and Dementia Unit at South London and Maudsley NHS Foundation Trust and King's College London and the National Institute for Health Research University College London Hospitals Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. A. H. receives support from the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement no115372, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007e2013) and EFPIA companies in kind contribution. R. D. is supported by awards to establish the Farr Institute of Health Informatics Research at UCL Partners, from the Medical Research Council, Arthritis Research UK, British Heart Foundation, Cancer Research UK, Chief Scientist Office, Economic and Social Research Council, Engineering and Physical Sciences Research Council, National Institute for Health Research, National Institute for Social Care and Health Research, and Wellcome Trust (grant MR/K006584/1)

Both traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) are common problems resulting from military service, and both have been associated with increased risk of cognitive decline and dementia resulting from Alzheimer's disease (AD) or o

AbstractBody mass index (BMI) is a risk factor for Alzheimer's disease (AD) although the relationship is complex. Obesity in midlife is associated with increased risk for AD, whereas evidence supports both higher and lower BMI increasing risk for AD in late life. This study examined the influence of individual differences in genetic risk for AD to further clarify the relationship between late-life BMI and conversion to AD. Participants included 52 individuals diagnosed as having mild cognitive impairment (MCI) at baseline who converted to AD within 24 months and 52 matched MCI participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. BMI was measured at baseline. Genetic risk for AD was assessed via genome-wide polygenic risk scores. Conditional logistic regression models were run to determine if BMI and polygenic risk predicted conversion to AD. Results showed an interaction between BMI and genetic risk, such that individuals with lower BMI and higher polygenic risk were more likely to convert to AD relative to individuals with higher BMI. These results remained significant after adjusting for cerebrospinal fluid biomarkers of AD. Exploratory sex-stratified analyses revealed this relationship only remained significant in males. These results show that higher genetic risk in the context of lower BMI predicts conversion to AD in the next 24 months, particularly among males. These findings suggest that genetic risk for AD in the context of lower BMI may serve as a prodromal risk factor for future conversion to AD.

INTRODUCTION: Alzheimer's disease (AD) represents a global health crisis. Treatments are needed to prevent, delay the onset, slow the progression, improve cognition, and reduce behavioral disturbances of AD. We review the current clinical trials and drugs in development for the treatment of AD. METHODS: We searched the governmental website clinicaltrials.gov where are all clinical trials conducted in the United States must be registered. We used artificial intelligence (AI) and machine learning (ML) approaches to ensure comprehensive detection and characterization of trials and drugs in development. We use the Common Alzheimer's Disease Research Ontology (CADRO) to classify drug targets and mechanisms of action of drugs in the pipeline. RESULTS: As of January 25, 2022 (index date for this study) there were 143 agents in 172 clinical trials for AD. The pipeline included 31 agents in 47 trials in Phase 3, 82 agents in 94 trials in Phase 2, and 30 agents in 31 trials in Phase 1. Disease‐modifying therapies represent 83.2% of the total number of agents in trials; symptomatic cognitive enhancing treatments represent 9.8% of agents in trials; and drugs for the treatment of neuropsychiatric symptoms comprise 6.9%. There is a diverse array of drug targets represented by agents in trials including nearly all CADRO categories. Thirty‐seven percent of the candidate agents in the pipeline are repurposed drugs approved for other indications. A total of 50,575 participants are needed to fulfill recruitment requirements for all currently active clinical trials. DISCUSSION: The AD drug development pipeline has agents representing a substantial array of treatment mechanisms and targets. Advances in drug design, outcome measures, use of biomarkers, and trial conduct promise to accelerate the delivery of new and better treatments for patients with AD. HIGHLIGHTS: There are 143 drugs in the current Alzheimer's disease (AD) drug development pipeline. Disease‐modifying therapies represent 83.2% of the candidate treatments. Current ...

Alzheimer's disease (AD) is a progressive neurodegenerative disease in which the formation of extracellular aggregates of amyloid beta (Aβ) peptide, fibrillary tangles of intraneuronal tau and microglial activation are major pathological hallmarks. One of the key molecules involved in microglial activation is galectin-3 (gal3), and we demonstrate here for the first time a key role of gal3 in AD pathology. Gal3 was highly upregulated in the brains of AD patients and 5xFAD (familial Alzheimer's disease) mice and found specifically expressed in microglia associated with Aβ plaques. Single-nucleotide polymorphisms in the LGALS3 gene, which encodes gal3, were associated with an increased risk of AD. Gal3 deletion in 5xFAD mice attenuated microglia-associated immune responses, particularly those associated with TLR and TREM2/DAP12 signaling. In vitro data revealed that gal3 was required to fully activate microglia in response to fibrillar Aβ. Gal3 deletion decreased the Aβ burden in 5xFAD mice and improved cognitive behavior. Interestingly, a single intrahippocampal injection of gal3 along with Aβ monomers in WT mice was sufficient to induce the formation of long-lasting (2 months) insoluble Aβ aggregates, which were absent when gal3 was lacking. High-resolution microscopy (stochastic optical reconstruction microscopy) demonstrated close colocalization of gal3 and TREM2 in microglial processes, and a direct interaction was shown by a fluorescence anisotropy assay involving the gal3 carbohydrate recognition domain. Furthermore, gal3 was shown to stimulate TREM2–DAP12 signaling in a reporter cell line. Overall, our data support the view that gal3 inhibition may be a potential pharmacological approach to counteract AD. ; This work was supported by Grants from the Swedish Research Council, and the Strong Research Environment MultiPark (Multidisciplinary Research in Parkinson's and Alzheimer's Disease at Lund University), Bagadilico (Linné consortium sponsored by the Swedish Research Council), the Swedish Alzheimer's Foundation, Swedish Brain Foundation, A.E. Berger Foundation, Gyllenstiernska Krapperup Foundation, the Royal Physiographic Society, Crafoord Foundation, Olle Engkvist Byggmästare Foundation, Wiberg Foundation, G&J Kock Foundation, Stohnes Foundation, Swedish Dementia Association and the Medical Faculty at Lund University. This work was supported by Grant SAF2015-64171R (Spanish MINECO/FEDER, UE), by Instituto de Salud Carlos III (ISCiii) of Spain, co-financed by FEDER funds from European Union through grants PI15/00796 and PI18/01557 (to AG), PI15/00957 and PI18/01556 (to JV), and CIBERNED (to AG and JV), by Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucia Proyecto de Excelencia (CTS-2035) (to JV and AG), and by Malaga University grant PPIT.UMA.B1.2017/26 (to RSV). AV and GCB received funding from the Innovative Medicines Initiative 2 Joint Undertaking under Grant agreement no. 115976 (PHAGO). CIBERNED "Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid (Spain)". HL and AF were supported by the Swedish Research Council, the Swedish Brain Foundation, the Alzheimer Foundation and the Åhlén Foundation. UJN was supported by Grants from the Knut and Alice Wallenberg Foundation (KAW 2013.0022) and the Swedish Research Council (Grant no. 621-2012-2978). ; Peer reviewed

This is the final version. Available from Elsevier via the DOI in this record. ; Genome-wide association studies (GWASs) have been effective approaches to dissect common genetic variability underlying complex diseases in a systematic and unbiased way. Recently, GWASs have led to the discovery of over 20 susceptibility loci for Alzheimer's disease (AD). Despite the evidence showing the contribution of these loci to AD pathogenesis, their genetic architecture has not been extensively investigated, leaving the possibility that low frequency and rare coding variants may also occur and contribute to the risk of disease. We have used exome and genome sequencing data to analyze the single independent and joint effect of rare and low-frequency protein coding variants in 9 AD GWAS loci with the strongest effect sizes after APOE (BIN1, CLU, CR1, PICALM, MS4A6A, ABCA7, EPHA1, CD33, and CD2AP) in a cohort of 332 sporadic AD cases and 676 elderly controls of British and North-American ancestry. We identified coding variability in ABCA7 as contributing to AD risk. This locus harbors a low-frequency coding variant (p.G215S, rs72973581, minor allele frequency = 4.3%) conferring a modest but statistically significant protection against AD (p-value = 0.024, odds ratio = 0.57, 95% confidence interval = 0.41-0.80). Notably, our results are not driven by an enrichment of loss of function variants in ABCA7, recently reported as main pathogenic factor underlying AD risk at this locus. In summary, our study confirms the role of ABCA7 in AD and provides new insights that should address functional studies. ; This study was supported by the Alzheimer's Research UK, the Medical Research Council (MRC), the Wellcome Trust/MRC Joint Call in Neurodegeneration award (WT089698) to the UK Parkinson's Disease Consortium (whose members are from the University College London Institute of Neurology, the University of Sheffield, and the MRC Protein Phosphorylation Unit at the University of Dundee), grants (P50 AG016574, U01 AG006786, and R01 AG18023), the National Institute for Health Research Biomedical Research Unit in Dementia at University College London Hospitals, University College London; an anonymous donor, the Big Lottery (to Dr. Morgan); a fellowship from Alzheimer's Research UK (to Dr. Guerreiro); and the Intramural Research Programs of the National Institute on Aging and the National Institute of Neurological Disease and Stroke, National Institutes of Health (Department of Health and Human Services Project number, ZO1 AG000950-10). The MRC London Neurodegenerative Diseases Brain Bank and the Manchester Brain Bank from Brains for Dementia Research are jointly funded from ARUK and AS. This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services, project number ZO1 AG000950-10. Samples from the National Cell Repository for Alzheimer's Disease (NCRAD), which receives government support under a cooperative agreement grant (U24 AG21886) awarded by the National Institute on Aging (NIA), were used in this study. NIH grant R01 AG042611 to Kauwe J.

Alzheimer's disease (AD) is a major health problem and a growing recognition exists that efforts to prevent it must be undertaken by both governmental and non-governmental organizations. In this context, the pineal product, melatonin, has a promising significance because of its chronobiotic/cytoprotective properties potentially useful for a number of aspects of AD. One of the features of advancing age is the gradual decrease in circulating melatonin levels. A limited number of therapeutic trials have indicated that melatonin has a therapeutic value as a neuroprotective drug in the treatment of AD and minimal cognitive impairment (which may evolve to AD). Both in vitro and in vivo, melatonin prevented the neurodegeneration seen in experimental models of AD. For these effects to occur, doses of melatonin about two orders of magnitude higher than those required to affect sleep and circadian rhythmicity are needed. More recently, attention has been focused on the development of potent melatonin analogs with prolonged effects, which were employed in clinical trials in sleep-disturbed or depressed patients in doses considerably higher than those employed for melatonin. In view that the relative potencies of the analogs are higher than that of the natural compound, clinical trials employing melatonin in the range of 50–100 mg/day are urgently needed to assess its therapeutic validity in neurodegenerative disorders such as AD.