Damage from free radicals has been demonstrated in susceptible neuronal populations in cases of Alzheimer disease. In this study, we investigated whether iron, a potent source of the highly reactive hydroxyl radical that is generated by the Fenton reaction with H 2 O 2 , might contribute to the source of radicals in Alzheimer disease. We found, using a modified histochemical technique that relies on the formation of mixed valence iron complexes, that redox-active iron is associated with the senile plaques and neurofibrillary tangles—the pathological hallmark lesions of this disease. This lesion-associated iron is able to participate in in situ oxidation and readily catalyzes an H 2 O 2 -dependent oxidation. Furthermore, removal of iron was completely effected using deferoxamine, after which iron could be rebound to the lesions. Characterization of the iron-binding site suggests that binding is dependent on available histidine residues and on protein conformation. Taken together, these findings indicate that iron accumulation could be an important contributor toward the oxidative damage of Alzheimer disease.
An article by Marcia Barinaga (Special Section, News, 28 Aug., p. [1303][1]) in the recent issue devoted to apoptosis presents the case for apoptotic neuronal death in Alzheimer's disease (AD) based on culture studies and histological analyses. We strongly disagree that this evidence supports widespread apoptosis in AD. Apoptosis requires only 16 to 24 hours for completion and, therefore, in a chronic disease like AD with an average duration of almost 10 years, less than one in about 4000 cells should be undergoing apoptosis at any given time (that is, observation of apoptotic events should be rare) ([1][2]). Indeed, if all the neurons reported with DNA cleavage were undergoing apoptosis, the brain would rapidly be stripped of neurons. This is certainly not the case in AD.
![Figure][3]
Do neurons in a brain from an Alzheimer's patient (dotlike staining pattern) indicate cells undergoing apoptosis?CREDIT: CARL COTMAN, JOSEPH SU, AND CHRISTIAN PIKE
Perhaps the greatest source of misunderstanding is that the criteria used for apoptosis have relied primarily on DNA fragmentation, where even the laddering pattern of fragmentation is not apoptosis-specific because histones protect DNA from a variety of insults, including those of necrosis and oxidative damage. When the more rigorous standard of nuclear condensation is examined, few neurons show apoptosis in AD. In fact, that we can observe neurons displaying many of the features of apoptosis argues that neurons in AD have mounted an effective defense to apoptotic death rather than that they are succumbing. The presence of a wide array of apoptotic markers is more likely indicative of an avoidance of apoptosis rather than actual completion of apoptosis. That neuronal cell death in AD occurs over a lengthy period suggests distinct mechanisms from the classical apoptotic process.
1. [↵][4]1. G. Perry, 2. A. Nunomura, 3. M. A. Smith
, Nature Med. 4, 897 (1998).
[OpenUrl][5][CrossRef][6][PubMed][7][Web of Science][8]
[1]: /lookup/doi/10.1126/science.281.5381.1303
[2]: #ref-1
[3]: pending:yes
[4]: #xref-ref-1-1 View reference 1 in text
[5]: {openurl}?query=rft.jtitle%253DNature%2Bmedicine%26rft.stitle%253DNat%2BMed%26rft.aulast%253DPerry%26rft.auinit1%253DG.%26rft.volume%253D4%26rft.issue%253D8%26rft.spage%253D897%26rft.epage%253D898%26rft.atitle%253DA%2Bsuicide%2Bnote%2Bfrom%2BAlzheimer%2Bdisease%2Bneurons%253F%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fnm0898-897%26rft_id%253Dinfo%253Apmid%252F9701239%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx
[6]: /lookup/external-ref?access_num=10.1038/nm0898-897&link_type=DOI
[7]: /lookup/external-ref?access_num=9701239&link_type=MED&atom=%2Fsci%2F282%2F5392%2F1265.8.atom
[8]: /lookup/external-ref?access_num=000075107400030&link_type=ISI
This paper details U.S. Research Centers in Minority Institutions (RCMI) Community Engagement Cores (CECs): (1) unique and cross-cutting components, focus areas, specific aims, and target populations; and (2) approaches utilized to build or sustain trust towards community participation in research. A mixed-method data collection approach was employed for this cross-sectional study of current or previously funded RCMIs. A total of 18 of the 25 institutions spanning 13 U.S. states and territories participated. CEC specific aims were to support community engaged research (94%); to translate and disseminate research findings (88%); to develop partnerships (82%); and to build capacity around community research (71%). Four open-ended questions, qualitative analysis, and comparison of the categories led to the emergence of two supporting themes: (1) establishing trust between the community-academic collaborators and within the community and (2) building collaborative relationships. An overarching theme, building community together through trust and meaningful collaborations, emerged from the supporting themes and subthemes. The RCMI institutions and their CECs serve as models to circumvent the historical and current challenges to research in communities disproportionately affected by health disparities. Lessons learned from these cores may help other institutions who want to build community trust in and capacities for research that addresses community-related health concerns.
Aging is a multi-factorial process, however, it is generally accepted that reactive oxygen species (ROS) are significant contributors. Mitochondria are important players in the aging process because they produce most of the cellular ROS. Despite the strength of the free-radical hypothesis, the use of free radical scavengers to delay aging has generated mixed results in vertebrate models, and clinical evidence of efficacy is lacking. This is in part due to the production of pro-oxidant metabolites by many antioxidants while scavenging ROS, which counteract their potentially beneficial effects. As such, a more effective approach is to enhance mitochondrial metabolism by reducing electron leakage with attendant reduction of ROS generation. Here, we report on the actions of a novel endogenous indole derivative, indolepropionamide (IPAM), which is similar in structure to melatonin. Our results suggest that IPAM binds to the rate-limiting component of oxidative phosphorylation in complex I of the respiratory chain and acts as a stabilizer of energy metabolism, thereby reducing ROS production. IPAM reversed the age-dependent decline of mitochondrial energetic capacity and increased rotifer lifespan, and it may, in fact, constitute a novel endogenous anti-aging substance of physiological importance.
Background Long non-coding RNAs (lncRNAs) have been reported to be involved in the pathogenesis of neurodegenerative diseases. It has also been hypothesized that plasma exosomal lncRNAs may be used as Alzheimer’s disease (AD) biomarkers. In this systematic review, we compiled all studies on the subject to evaluate the accuracy of lncRNAs in identifying AD cases through meta-analysis. Methods A PRISMA-compliant systematic search was conducted in PubMed/MEDLINE, EMBASE, and Web of Science databases for English publications till September 2022. We included all observational studies published which investigated the sensitivity and specificity of various lncRNAs in plasma samples of AD diagnosis. Our search strategy included lncRNA and all the related spelling and abbreviation variations combined with the keyword Alzheimer’s disease. Methodological quality was assessed using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines and the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-II) tool. The meta-analysis was carried out using the area under the Receiver Operator Characteristic (ROC) curves (AUC) and sensitivity and specificity values to assess the accuracy of the identified lncRNAs in AD diagnosis. To account for the predicted heterogeneity of the study, a random-effects model was used. All the statistical analyses and visualizations were conducted using Stata 17.0 software. Results A total of seven studies (AD patients = 553, healthy controls = 513) were included in the meta-analysis. Three lncRNAs were upregulated (RNA BACE-AS1, RNA NEAT1, RNA GAS5), and one lncRNA (MALAT1) was downregulated in plasma samples of AD patients. RNA 51A and RNA BC200 were reported to have variable expression patterns. A lncRNA (RNA 17A) was not significantly different between AD and control groups. The pooled sensitivity, specificity, and AUC values of lncRNAs in identifying AD were (0.74; 95% CI [0.63, 0.82], I2 = 79.2%), (0.88; 95% CI [0.75, 0.94], I2 = 88.9%), and 0.86; 95% CI [0.82, 0.88], respectively. In addition, the pooled diagnostic odds ratio (DOR) of the five individual lncRNAs in AD diagnosis was 20. Conclusion lncRNAs had high accuracy in identifying AD and must be seen as a promising diagnostic biomarker of the disease.
'%3e%3cpath fill='%23012169' d='M0 0v30h60V0z'/%3e%3cpath stroke='%23fff' stroke-width='6' d='m0 0 60 30m0-30L0 30'/%3e%3cpath stroke='%23C8102E' stroke-width='4' d='m0 0 60 30m0-30L0 30' clip-path='url(%23b)'/%3e%3cpath stroke='%23fff' stroke-width='10' d='M30 0v30M0 15h60'/%3e%3cpath stroke='%23C8102E' stroke-width='6' d='M30 0v30M0 15h60'/%3e%3c/g%3e%3c/svg%3e)