IU Indianapolis ScholarWorks :: Browsing by Subject "Alzheimer"

Browsing by Subject "Alzheimer"

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Amyloid polymorphisms constitute distinct clouds of conformational variants in different etiological subtypes of Alzheimer's disease
(National Academy of Sciences, 2017-12-05) Rasmussen, Jay; Mahler, Jasmin; Beschorner, Natalie; Kaeser, Stephan A.; Häsler, Lisa M.; Baumann, Frank; Nyström, Sofie; Portelius, Erik; Blennow, Kaj; Lashley, Tammaryn; Fox, Nick C.; Sepulveda-Falla, Diego; Glatzel, Markus; Oblak, Adrian L.; Ghetti, Bernardino; Nilsson, K. Peter R.; Hammarström, Per; Staufenbiel, Matthias; Walker, Lary C.; Jucker, Mathias; Pathology and Laboratory Medicine, School of Medicine
The molecular architecture of amyloids formed in vivo can be interrogated using luminescent conjugated oligothiophenes (LCOs), a unique class of amyloid dyes. When bound to amyloid, LCOs yield fluorescence emission spectra that reflect the 3D structure of the protein aggregates. Given that synthetic amyloid-β peptide (Aβ) has been shown to adopt distinct structural conformations with different biological activities, we asked whether Aβ can assume structurally and functionally distinct conformations within the brain. To this end, we analyzed the LCO-stained cores of β-amyloid plaques in postmortem tissue sections from frontal, temporal, and occipital neocortices in 40 cases of familial Alzheimer's disease (AD) or sporadic (idiopathic) AD (sAD). The spectral attributes of LCO-bound plaques varied markedly in the brain, but the mean spectral properties of the amyloid cores were generally similar in all three cortical regions of individual patients. Remarkably, the LCO amyloid spectra differed significantly among some of the familial and sAD subtypes, and between typical patients with sAD and those with posterior cortical atrophy AD. Neither the amount of Aβ nor its protease resistance correlated with LCO spectral properties. LCO spectral amyloid phenotypes could be partially conveyed to Aβ plaques induced by experimental transmission in a mouse model. These findings indicate that polymorphic Aβ-amyloid deposits within the brain cluster as clouds of conformational variants in different AD cases. Heterogeneity in the molecular architecture of pathogenic Aβ among individuals and in etiologically distinct subtypes of AD justifies further studies to assess putative links between Aβ conformation and clinical phenotype.
Blood-based biomarkers for Alzheimer's disease
(EMBO Press, 2022) Leuzy, Antoine; Mattsson-Carlgren, Niklas; Palmqvist, Sebastian; Janelidze, Shorena; Dage, Jeffrey L.; Hansson, Oskar; Neurology, School of Medicine
Neurodegenerative disorders such as Alzheimer's disease (AD) represent a mounting public health challenge. As these diseases are difficult to diagnose clinically, biomarkers of underlying pathophysiology are playing an ever‐increasing role in research, clinical trials, and in the clinical work‐up of patients. Though cerebrospinal fluid (CSF) and positron emission tomography (PET)‐based measures are available, their use is not widespread due to limitations, including high costs and perceived invasiveness. As a result of rapid advances in the development of ultra‐sensitive assays, the levels of pathological brain‐ and AD‐related proteins can now be measured in blood, with recent work showing promising results. Plasma P‐tau appears to be the best candidate marker during symptomatic AD (i.e., prodromal AD and AD dementia) and preclinical AD when combined with Aβ42/Aβ40. Though not AD‐specific, blood NfL appears promising for the detection of neurodegeneration and could potentially be used to detect the effects of disease‐modifying therapies. This review provides an overview of the progress achieved thus far using AD blood‐based biomarkers, highlighting key areas of application and unmet challenges.
EMF Antenna Exposure on a Multilayer Human Head Simulation for Alzheimer Disease Treatments
(Scientific Research, 2022) Perez, Felipe P.; Rahmani, Maryam; Emberson, John; Weber, Makenzie; Morisaki, Jorge; Amran, Farhan; Bakri, Syazwani; Halim, Akmal; Dsouza, Alston; Yusuff, Nurafifi Mohd; Farhan, Amran; Maulucci, James; Rizkalla, Maher; Medicine, School of Medicine
In this paper, we follow up with our preliminary biological studies that showed that Repeated electromagnetic field stimulation (REMFS) decreased the toxic amyloid-beta (Aβ) levels, which is considered to be the cause of Alzheimer's disease (AD). The REMFS parameters of these exposures were a frequency of 64 MHz and a Specific absorption rate (SAR) of 0.4 to 0.9 W/Kg in primary human neuronal cultures. In this work, an electromagnetic field (EMF) model was simulated using high-frequency simulation system (HFSS/EMPro) software. Our goal was to achieve the EM parameters (EMF Frequency and SAR) required to decrease the toxic Aβ levels in our biological studies in a simulated human head. The simulations performed here will potentially lead to the successful development of an exposure system to treat Alzheimer's disease patients. A popular VFH (very high frequency) patch microstrip antenna system was considered in the study. The selection was based on simple and easy construction and appropriateness to the VHF applications. The evaluation of the SAR and temperature distribution on the various head layers, including skin, fat, dura, the cerebrospinal (CSF), and grey matter, brain tissues, were determined for efficacy SAR and safety temperature increase on a simulated human head. Based on a current pulse of 1 A peak current fed to the antenna feeder, a maximum SAR of 0.6 W/Kg was achieved. A range of 0.4 to 0.6 SAR was observed over the various layers of the simulated human head. The initial design of the antenna indicated an antenna size in the order of 1 m in length and width, suggesting a stationary practical model for AD therapy. Future direction is given for wearable antenna and exposure system, featuring high efficiency and patient comfort.
EVALUATION OF GENE REGULATION AND THERAPEUTIC DRUGS RELATED TO ALZHEIMER’S DISEASE IN DEGENERATING PRIMARY CEREBROCORTICAL CULTURES
(2012-03-16) Bailey, Jason A.; Lahiri, Debomoy K.; Du, Yansheng; McBride, William J., 1956-; Zhou, Feng
Alzheimer’s disease (AD) is a neurological disorder defined by the presence of plaques comprised mostly of amyloid-β (Aβ), and neurofibrillary tangles consisting of hyperphosphorylated microtubule associated protein tau (MAPT). AD is also characterized by widespread synapse loss and degeneration followed by death of neurons in the brain. Inflammatory processes, such as glial activation, are also implicated. In order to study mechanisms of neurodegeneration and evaluate potential therapeutic agents that could slow or reverse this process, a tissue culture system was developed based on primary embryonic cerebrocortical neurons. This culture system was observed to exhibit time-dependent neurodegeneration, glial proliferation, and synaptic marker loss consistent with AD-affected brains. The regulatory promoter regions of several genes implicated in AD, including the Aβ precursor protein (APP), β-amyloid cleaving enzyme (BACE1), and MAPT, were studied in this culture model. The MAPT gene promoter activity followed the pattern of neuronal maturation and degeneration quite closely, increasing in the initial phase of the tissue culture, then reducing markedly during neurodegeneration while APP and BACE1 gene promoters remained active. Deletion series of these promoters were tested to give an initial indication of the active regions of the gene promoter regions. Furthermore, the effects of exogenous Aβ and overexpression of p25, which are two possible pathogenic mechanisms of gene regulation in AD, were studied. Response to Aβ varied between the promoters and by length of the Aβ fragment used. Overexpression of p25 increased MAPT, but not APP or BACE1, promoter activity. This neurodegeneration model was also used to study the putative neuroprotective action of the NMDA receptor antagonist memantine. Treatment with memantine prevented loss of synaptic markers and preserved neuronal morphology, while having no apparent effect on glial activation. The protective action on synaptic markers was also observed with two other structurally distinct NMDA receptor antagonists, suggesting that the effects of memantine are produced by its action on the NMDA receptor. It is concluded that this tissue culture model will be useful for the study of gene regulation and therapeutic agents for neurodegeneration, and that the efficacy of memantine may result from preservation of synaptic connections in the brain.
Lipidomic Dysregulation in Alzheimer's Disease: Relation to Genetics, Neuroimaging and Other Biomarkers
(2021-04) Bernath, Megan M.; Saykin, Andrew J.; Nho, Kwangsik; Herbert, Brittney-Shea; Lahiri, Debomoy K.; Lamb, Bruce T.; Risacher, Shannon L.
Large-scale genome-wide association studies for Alzheimer’s disease (AD) have identified more than 20 risk loci and several pathways including lipid metabolism. Lipids are fundamental to cellular structure and organization, where they compose biological bilayer membranes surrounding the cell. In their structural role, lipids provide a scaffold for cell signaling, such as neurotransmission. There is a large body of evidence linking lipids and AD, yet the relationship between AD pathogenesis and lipid dyshomeostasis is not well understood. Here, we performed manual PubMed searches to identify the most studied lipid classes and risk genes in AD. We discussed pathological alterations of the key lipids and their potential contribution to the recent NIA-AA “A/T/N” framework. We also summarized what is known between the key lipids and etiological hypotheses of AD. Finally, we characterized relationship of the key lipids with AD genomic risk factors to identify possible downstream mechanisms of lipid dysfunction in AD. There is a large body of evidence linking lipids and AD, yet the relationship between AD pathogenesis and lipid dyshomeostasis is not well understood. In particular, we investigated the association between triglyceride (TG) species and AD. The overall goal was to test the hypothesis that TGs would associate with AD endophenotypes, based on their fatty acid composition. Diagnostic groups (cognitively normal older adults (CN), mild cognitive impairment (MCI), and AD) differed on two principal components extracted from 84 serum TG levels. Fish oil-type and olive oil-type TGs were significantly lower in MCI and AD compared to CN. Next, association analysis of TG principal components with “A/T/N/V” (amyloid-β, tau, neurodegeneration, and cerebrovascular) biomarkers for AD showed that the fish oil-type and olive oil-type TGs were also significantly associated with atrophy on MRI. Finally, a mixed model regression analysis investigated the association between baseline TGs and longitudinal changes of AD endophenotypes to show that olive oil-type TGs predicted changes in AD brain atrophy. Our results indicate that a specific subcategory of TGs is associated with an early prodromal stage of cognitive impairment and early-stage biomarkers for AD, providing the foundation for future therapeutic development related to TG metabolism.
Loss of Inpp5d has disease‐relevant and sex‐specific effects on glial transcriptomes
(Wiley, 2024) Dabin, Luke C.; Kersey, Holly; Kim, Byungwook; Acri, Dominic J.; Sharify, Daniel; Lee-Gosselin, Audrey; Lasagna-Reeves, Cristian A.; Oblak, Adrian L.; Lamb, Bruce T.; Kim, Jungsu; Medical and Molecular Genetics, School of Medicine
Introduction: Inpp5d is genetically associated with Alzheimer's disease risk. Loss of Inpp5d alters amyloid pathology in models of amyloidosis. Inpp5d is expressed predominantly in microglia but its function in brain is poorly understood. Methods: We performed single-cell RNA sequencing to study the effect of Inpp5d loss on wild-type mouse brain transcriptomes. Results: Loss of Inpp5d has sex-specific effects on the brain transcriptome. Affected genes are enriched for multiple neurodegeneration terms. Network analyses reveal a gene co-expression module centered around Inpp5d in female mice. Inpp5d loss alters Pleotrophin (PTN), Prosaposin (PSAP), and Vascular Endothelial Growth Factor A (VEGFA) signaling probability between cell types. Discussion: Our data suggest that the normal function of Inpp5d is entangled with mechanisms involved in neurodegeneration. We report the effect of Inpp5d loss without pathology and show that this has dramatic effects on gene expression. Our study provides a critical reference for researchers of neurodegeneration, allowing separation of disease-specific changes mediated by Inpp5d in disease from baseline effects of Inpp5d loss. Highlights: Loss of Inpp5d has different effects in male and female mice. Genes dysregulated by Inpp5d loss relate to neurodegeneration. Total loss of Inpp5d in female mice collapses a conserved gene co-expression module. Loss of microglial Inpp5d affects the transcriptome of other cell types.
The microrna-mediated regulation of proteins implicated in the pathogenesis of Alzheimer's Disease
(2016-11-29) Chopra, Nipun; Zhou, Feng; Lahiri, Debomoy K.; Hashino, Eri; Obukhov, Alexander
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the post-mortem deposition of amyloid-beta (Aβ) containing neuritic plaques and tau-loaded tangles. According to the amyloid hypothesis, the generation of Aβ via the cleavage of Aβ precursor protein (APP) by β-APP site-cleaving enzyme 1 (BACE1) is a causative step in the development of AD. Therefore, targeting the production and/or clearance of Aβ peptide (by Aβ-degrading enzymes such as Neprilysin) would help understand the disorder as well as serves as therapeutic potential to treat the disorder. MicroRNA are small, noncoding RNA capable of modulating protein expression by primarily targeting their 3’UTR. Therefore, identifying miRNA which target APP, BACE1 and Neprilysin (NEP) would elucidate the complicated regulatory mechanisms involved in protein turnover and provide novel drug targets. We identified miR-20b as a modulator of APP and soluble Aβ. We also identified the target site for miR-20b’s binding on the APP 3’UTR. Further, miR-20b exerts influence on neuronal morphology, likely due to its APP reduction. We also identified miR-298 as a dual regulator of APP and BACE1 and confirmed miR-298’s targeting of both 3’UTRs. We also showed that miR-298 overexpression reduced levels of both soluble Aβ40 and Aβ42 peptides. Additionally, we identified two SNPs in proximity to the MIR298 gene, which are associated with AD-related biomarkers. Based on these results, we showed miR-298 targets a specific isoform of tau by putatively binding a non-canonical target site on the MAPT 3’UTR. Finally, the insertion of the NEP 3’UTR into a reporter vector increases reporter expression; suggesting regulatory elements targeting the 3’UTR. We subsequently identified miR-216 as reducing NEP 3’UTR-mediated luciferase activity. We also measured levels of NEP protein in various mammalian tissue – such as rodent and human fetal tissue, and subsequently showed measurable Aβ levels in correlation with NEP expression. Therefore, herein, we have identified miRNA involved in the regulation of proteins implicated in the pathogenesis of AD.
Novel regulation of neuronal genes implicated in Alzheimer disease by microRNA
(2013-12-11) Long, Justin M.; Zhou, Feng C.; Lahiri, Debomoy K.; Farlow, Martin R.; Nass, Richard M.; Du, Yansheng
Alzheimer disease (AD) results, in part, from the excess accumulation of the amyloid-β peptide (Aβ) as neuritic plaques in the brain. The short Aβ peptide is derived from a large transmembrane precursor protein, APP. Two different proteolytic enzymes, BACE1 and the gamma-secretase complex, are responsible for cleaving Aβ peptide from APP through an intricate processing pathway. Dysregulation of APP and BACE1 levels leading to excess Aβ deposition has been implicated in various forms of AD. Thus, a major goal in this dissertation was to discover novel regulatory pathways that control APP and BACE1 expression as a means to identify novel drug targets central to the Aβ-generating process. MicroRNAs (miRNA) are short, non-coding RNAs that act as post-transcriptional regulators of gene expression through specific interactions with target mRNAs. Global analyses predict that over sixty percent of human transcripts contain evolutionarily conserved miRNA target sites. Therefore, the specific hypothesis tested was that miRNA are relevant regulators of APP and BACE1 expression. In this work, several specific miRNA were identified that regulate APP protein expression (miR-101, miR-153 and miR-346) or BACE1 expression (miR-339-5p). These miRNAs mediated their post-transcriptional effects via interactions with specific target sites in the APP and BACE1 transcripts. Importantly, these miRNA also altered secretion of Aβ peptides in primary human fetal brain cultures. Surprisingly, miR-346 stimulated APP expression via target sites in the APP 5’-UTR. The mechanism of this effect appears to involve other RNA-binding proteins that bind to the APP 5’-UTR. Expression analyses demonstrated that these miRNAs are expressed to varying degrees in the human brain. Notably, miR-101, miR-153 and miR-339-5p are dysregulated in the AD brain at various stages of the disease. The work in this dissertation supports the hypothesis that miRNAs are important regulators of APP and BACE1 expression and are capable of altering Aβ homeostasis. Therefore, these miRNA may possibly serve as novel therapeutic targets for AD.
Topographic staging of tau positron emission tomography images
(Elsevier, 2018-02-14) Schwarz, Adam J.; Shcherbinin, Sergey; Slieker, Lawrence J.; Risacher, Shannon L.; Charil, Arnaud; Irizarry, Michael C.; Fleisher, Adam S.; Southekal, Sudeepti; Joshi, Abhinay D.; Devous, Michael D., Sr.; Miller, Bradley B.; Saykin, Andrew J.; Alzheimer's Disease Neuroimaging Initiative; Radiology and Imaging Sciences, School of Medicine
Introduction: It has been proposed that the signal distribution on tau positron emission tomography (PET) images could be used to define pathologic stages similar to those seen in neuropathology. Methods: Three topographic staging schemes for tau PET, two sampling the temporal and occipital subregions only and one sampling cortical gray matter across the major brain lobes, were evaluated on flortaucipir F 18 PET images in a test-retest scenario and from Alzheimer's Disease Neuroimaging Initiative 2. Results: All three schemes estimated stages that were significantly associated with amyloid status and when dichotomized to tau positive or negative were 90% to 94% concordant in the populations identified. However, the schemes with fewer regions and simpler decision rules yielded more robust performance in terms of fewer unclassified scans and increased test-retest reproducibility of assigned stage. Discussion: Tau PET staging schemes could be useful tools to concisely index the regional involvement of tau pathology in living subjects. Simpler schemes may be more robust.

Browsing by Subject "Alzheimer"

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