Cholesterol-transporting protein most notably implicated in Alzheimer's disease
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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.13.520238v1?rss=1 Authors: Konings, S. C., Nyberg, E., Martinsson, I., Torres-Garcia, L., Guimas Almeida, C., Gouras, G. K. Abstract: Apolipoprotein E4 (ApoE4) is the most important genetic risk factor for Alzheimer's disease (AD). Among the earliest changes in AD is endosomal enlargement in neurons, which was reported as enhanced in ApoE4 carriers. ApoE is thought to be internalized into endosomes of neurons, while {beta}-amyloid (A{beta}) accumulates within neuronal endosomes early in AD. However, it remains unknown whether ApoE and A{beta} intersect intracellularly. We show that internalized astrocytic ApoE localizes mostly to lysosomes in neuroblastoma cells and astrocytes, while in neurons it preferentially localizes to endosomes-autophagosomes of neurites. In AD transgenic neurons, astrocyte-derived ApoE intersects intracellularly with amyloid precursor protein (APP)/A{beta}. Moreover, ApoE4 increases the levels of endogenous and internalized A{beta}42 in neurons. Taken together, we demonstrate differential localization of ApoE in neurons, astrocytes and neuron-like cells, and show that internalized ApoE intersects with APP/A{beta} in neurons, which may be of considerable relevance to AD. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
This episode is dedicated to clarification of a podcast between Joe Rogan and Max Lugavere, two popular influencers that have a large audience. They discussed Alzheimer's disease and brain health in general and some of the information that was shared was not accurate, which can be really harmful. This is by no means an attack on Rogan or Lugavere. After listening to the conversation, we think Lugavere may not be quite familiar with the data regarding brain health, and it would be important to set the record straight and share the evidence with people and let them decide what's best for them. Having seen thousands of patients with dementia, whether it's Alzheimer's disease, frontotemporal lobe dementia, Lewy Body Dementia and others, we feel it's our responsibility to share evidence based data as opposed to feel-good, self confirming anecdotes. Relevant references: Ketogenic Diet: Phillips, M. C et al. (2021). Randomized crossover trial of a modified ketogenic diet in Alzheimer's disease. Alzheimer's research & therapy, 13(1), 1-12. Lilamand, M et al. (2022). Efficacy and Safety of Ketone Supplementation or Ketogenic Diets for Alzheimer's Disease: A Mini Review. Frontiers in Nutrition, 1324. Włodarek, D. (2021). Food for thought: the emerging role of a ketogenic diet in Alzheimer's disease management. Expert Review of Neurotherapeutics, 21(7), 727-730. Cronjé, H et al. (2021). Ketogenic therapies in mild cognitive impairment and dementia. Current Opinion in Lipidology, 32(5), 330-332. LDL Cholesterol metabolism and risk of Alzheimer's: Andrews, S et al., collaborators of the Alzheimer's Disease Genetics Consortium. (2021). Causal associations between modifiable risk factors and the Alzheimer's phenome. Annals of neurology, 89(1), 54-65. Olmastroni, E et al. (2022). Statin use and risk of dementia or Alzheimer's disease: a systematic review and meta-analysis of observational studies. European Journal of Preventive Cardiology, 29(5), 804-814. Iwagami, M et al. (2021). Blood cholesterol and risk of dementia in more than 1· 8 million people over two decades: a retrospective cohort study. The Lancet Healthy Longevity, 2(8), e498-e506. Tan, Z. S et al. (2003). Plasma total cholesterol level as a risk factor for Alzheimer disease: the Framingham Study. Archives of Internal Medicine, 163(9), 1053-1057. Kivipelto, M et al. (2002). Apolipoprotein E ε4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease. Annals of internal medicine, 137(3), 149-155. Zhou, Z et al. (2020). Low-density lipoprotein cholesterol and Alzheimer's disease: a systematic review and meta-analysis. Frontiers in aging neuroscience, 12, 5. Sáiz-Vazquez, O et al. (2020). Cholesterol and Alzheimer's disease risk: a meta-meta-analysis. Brain sciences, 10(6), 386. Wingo, A. P et al. (2022). LDL cholesterol is associated with higher AD neuropathology burden independent of APOE. Journal of Neurology, Neurosurgery & Psychiatry, 93(9), 930-938. The Nigerian Paradox Study: Hall, K et al. (2006). Cholesterol, APOE genotype, and Alzheimer disease: an epidemiologic study of Nigerian Yoruba. Neurology, 66(2), 223-227. Vascular health and Alzheimer's disease: Levit, A et al. (2020). Neurovascular unit dysregulation, white matter disease, and executive dysfunction: the shared triad of vascular cognitive impairment and Alzheimer disease. Geroscience, 42(2), 445-465. The Effect of Lifestyle on Alzheimer's Risk: Dhana, K et al. (2020). Healthy lifestyle and the risk of Alzheimer dementia: Findings from 2 longitudinal studies. Neurology, 95(4), e374-e383. Risk Reduction of Cognitive Decline and Dementia: WHO Guidelines. Geneva, Switzerland: World Health Organization; 2019. https://apps.who.int/iris/bitstream/handle/10665/312180/9789241550543-eng.pdf. Accessed December 4, 2019. MIND Diet: Morris, M. C et al. (2015). MIND diet associated with reduced incidence of Alzheimer's disease. Alzheimer's & Dementia, 11(9), 1007-1014. Morris, M. C et al. (2015). MIND diet slows cognitive decline with aging. Alzheimer's & dementia, 11(9), 1015-1022. van den Brink, A. C et al. (2019). The Mediterranean, Dietary Approaches to Stop Hypertension (DASH), and Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diets are associated with less cognitive decline and a lower risk of Alzheimer's disease—a review. Advances in Nutrition, 10(6), 1040-1065. Kheirouri, S., & Alizadeh, M. (2021). MIND diet and cognitive performance in older adults: a systematic review. Critical Reviews in Food Science and Nutrition, 1-19. Hosking, D. E et al. (2019). MIND not Mediterranean diet related to 12-year incidence of cognitive impairment in an Australian longitudinal cohort study. Alzheimer's & Dementia, 15(4), 581-589. Melo van Lent, D et al. (2021). Mind diet adherence and cognitive performance in the Framingham heart study. Journal of Alzheimer's Disease, 82(2), 827-839. Dhana, K et al. (2021). MIND diet, common brain pathologies, and cognition in community-dwelling older adults. Journal of Alzheimer's Disease, 83(2), 683-692. Thomas, A et al. (2022). Association of a MIND Diet with Brain Structure and Dementia in a French Population. The Journal of Prevention of Alzheimer's Disease, 1-10. Arjmand, G et al. (2022). Effect of MIND diet intervention on cognitive performance and brain structure in healthy obese women: a randomized controlled trial. Scientific Reports, 12(1), 1-14. Nutrition and Dementia Prevention: Yassine, H. N et al. (2022). Nutrition state of science and dementia prevention: recommendations of the Nutrition for Dementia Prevention Working Group. The Lancet Healthy Longevity, 3(7), e501-e512. Scarmeas, N et al. (2018). Nutrition and prevention of cognitive impairment. The Lancet Neurology, 17(11), 1006-1015. Publications by Lugavere's mentor, Dr. Richard Isaacson: Isaacson, R. S et al. (2019). Individualized clinical management of patients at risk for Alzheimer's dementia. Alzheimer's & Dementia, 15(12), 1588-1602. Amini, Y., Saif, N., Greer, C., Hristov, H., & Isaacson, R. (2020). The role of nutrition in individualized Alzheimer's risk reduction. Current nutrition reports, 9(2), 55-63. Isaacson, R. S. (2019). Advances in early diagnosis and treatment strategies in the management of Alzheimer's disease. Journal of Managed Care Medicine, 22(4), 17-21. Berkowitz, C. L., Mosconi, L., Rahman, A., Scheyer, O., Hristov, H., & Isaacson, R. S. (2018). Clinical application of APOE in Alzheimer's prevention: a precision medicine approach. The journal of prevention of Alzheimer's disease, 5(4), 245-252. BOOK: The Alzheimer's Prevention & Treatment Diet: Using Nutrition to Combat the Effects of Alzheimer's Disease. Isaacson, R. S., & Ochner, C. N. (2016). Square One Publishers, Inc. Podcast episodes mentioned: The Proof with Simon Hill: The carnivore diet, veganism and nutrition misinformation | Dr Alan Flanagan. The Proof with Simon Hill: Debate: Seed Oils And Heart Disease | Tucker Goodrich And Dr Matthew Nagra Our publications relevant to this topic: Sherzai, A., Edland, S. D., Masliah, E., Hansen, L., Pizzo, D. P., Sherzai, A., & Corey-Bloom, J. (2013). Spongiform change in dementia with Lewy bodies and Alzheimer disease. Alzheimer Disease & Associated Disorders, 27(2), 157-161. Whitehair, D. C., Sherzai, A., Emond, J., Raman, R., Aisen, P. S., Petersen, R. C., & Fleisher, A. S. (2010). Influence of apolipoprotein E ɛ4 on rates of cognitive and functional decline in mild cognitive impairment. Alzheimer's & Dementia, 6(5), 412-419. Lazar, E., Sherzai, A., Adeghate, J., & Sherzai, D. (2021). Gut dysbiosis, insulin resistance and Alzheimer's disease: review of a novel approach to neurodegeneration. Frontiers in Bioscience-Scholar, 13(1), 17-29. Sherzai, D., & Sherzai, A. (2019). Preventing Alzheimer's: Our most urgent health care priority. American journal of lifestyle medicine, 13(5), 451-461. Sherzai, A. Z., Sherzai, A. N., & Sherzai, D. (2022). A Systematic Review of Omega-3 Consumption and Neuroprotective Cognitive Outcomes. American Journal of Lifestyle Medicine, 15598276221117102. Sherzai, D., Sherzai, A., & Sherzai, A. (2022). Lifestyle Intervention and Alzheimer Disease. The Journal of Family Practice, 71(1 Suppl Lifestyle), eS83-eS89. Sherzai, D., Sherzai, A., Lui, K., Pan, D., Chiou, D., Bazargan, M., & Shaheen, M. (2016). The association between diabetes and dementia among elderly individuals: a nationwide inpatient sample analysis. Journal of Geriatric Psychiatry and Neurology, 29(3), 120-125. Sherzai, A., Sherzai, D., Pilot, M., & Ovbiagele, B. (2016). Prevalence of the Diagnoses of Alzheimer's Dementia, Non-Alzheimer's Dementia and Vascular Dementia Among Hospitalized Stroke Patients: A National Inpatient Sample Analysis, 1999-2012 (P1. 125). Follow us on social media: Instagram: The Brain Docs @thebraindocs Facebook: The Brain Docs Website: TheBrainDocs.com
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.09.01.506258v1?rss=1 Authors: Smith, A. E., Chau, A., Greaves, D., Keage, H., Feuerriegel, D. C. Abstract: We investigated how resting EEG measures are associated with risk factors for late-life cognitive impairment and dementia, including age, Apolipoprotein E e4 (APOE-e4) carriage and cardiometabolic burden. Resting EEG was recorded from 86 adults (50-80 years of age). Participants additionally completed the Addenbrookes Cognitive Examination (ACE) III and had blood drawn to assess APOE-e4 carriage status and cardiometabolic burden. EEG power spectra were decomposed into sources of periodic and aperiodic activity to derive measures of aperiodic component slope and alpha (7-14 Hz) and beta (15-30 Hz) peak power and peak frequency. The aperiodic component slope was correlated with ACE-III scores but not age. Alpha peak frequency decreased with age. Individuals with higher cardiometabolic burden had lower alpha peak frequencies and lower beta peak power. APOE-e4 carriers had lower beta peak frequencies. Our findings suggest that the slope of the aperiodic component of resting EEG power spectra is more closely associated with cognitive performance (which generally declines with age) rather than chronological age, where these have been conflated in previous work. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer
Apolipoprotein E is a protein involved in the metabolism of fats in the body of mammals. The ApoE4 subtype is the most well known genetic risk factor for Alzheimer's disease. It is also implicated in cardiovascular disease, stroke, Parkinson's, Lewy body dementia, multiple sclerosis, and other aging-associated diseases. The underlying pathologic role of the APOE alleles may be understood in terms of its metabolic impact during aging, which has implications for optimizing our diet. Julie Gregory is the founder and president of the ApoE4.Info non-profit, a grassroots organization of ApoE4 carriers working to prevent and reverse Alzheimer's disease. Julie also serves as the Chief Health Liaison for Apollo Health and shares her expertise through ApoE4 Consulting, LLC. Julie recently teamed up with Dr. Dale Bredesen and his integrative physician wife, Aida Lasheen Bredesen, MD to share the diet and lifestyle strategies she uses in the book, The End of Alzheimer's Program: The First Protocol to Enhance Cognition and Reverse Decline at Any Age. Apoe4.info*** CONNECT WITH ROBERT LUFKIN MD ON SOCIAL MEDIA ***Web: https://robertlufkinmd.com/ Twitter:https://twitter.com/robertlufkinmdYoutube: https://www.youtube.com/RobertLufkinMD*** GOT A SUGGESTION FOR A SHOW? ***Contact us at: https://robertlufkinmd.com/contact *** SPONSORSHIPS & BRANDS ***We do work with sponsors and brands. If you are interested in working with us for your health industry product or service, please contact us at: https://robertlufkinmd.com/contact NOTE: This is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have. Never disregard professional medical advice or delay in seeking it because of something you have seen here. Robert Lufkin MD may at any time and at its sole discretion change or replace the information available on this channel. To the extent permitted by mandatory law, Robert Lufkin MD shall not be liable for any direct, incidental, consequential, indirect or punitive damages arising out of access to or use of any content available on this channel, including viruses, regardless of the accuracy or completeness of any such content.Disclaimer: We are ambassadors or affiliates for many of the brands we reference on the channel.Support the show (https://robert-lufkin.mykajabi.com/membership)
In today’s episode we are joined by A Month in Neurodegenerative Disease Research’s Sarah Louadi and Elyn Rowe to talk about neurodegenerative research, Alzheimer’s Disease, and AMiNDR Podcast. Elyn shares with us how heart health is related to Alzheimer’s Disease, and how good cholesterol might help identify, prevent, and treat Alzheimer’s Disease. Sarah explains how trying to keep up with the incredible volume of literature on neurodegenerative research inspired the creation of AMiNDR podcast. How do you diagnose Alzheimer’s Disease? What is Apolipoprotein E? How can we keep up with the onslaught of new and exciting literature? All this and much more in A Month in Neurodegenerative Disease Research with Sarah Louadi and Elyn Rowe!Listen to Part Two of this episode, in which Drake and Kyle join Sarah and Elyn to talk about Brain Buzz Podcast, at AMiNDR.com!
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.19.345991v1?rss=1 Authors: Johnson, L. A. Abstract: Cerebral glucose hypometabolism is consistently observed in individuals with Alzheimers disease, as well as in young cognitively normal carriers of the E4 allele of Apolipoprotein E, the strongest genetic predictor of late-onset AD. While this clinical feature has been described for over two decades, the mechanism underlying these changes in cerebral glucose metabolism remains a critical knowledge gap in the field. Here, we undertook a multi-omic approach by combining single-cell RNA sequencing and stable isotope resolved metabolomics to define a metabolic rewiring across astrocytes, brain tissue, mice, and human subjects expressing APOE4. Single-cell analysis of brain tissue from mice expressing human APOE revealed E4-associated decreases in genes related to oxidative phosphorylation, particularly in astrocytes. This shift was confirmed on a metabolic level with isotopic tracing of 13C-glucose in E4 mice and astrocytes, which showed decreased pyruvate entry into the TCA cycle and increases in lactate synthesis. Metabolic phenotyping of E4 astrocytes showed elevated glycolytic activity, decreased oxygen consumption, blunted oxidative flexibility, and a lower rate of glucose oxidation in the presence of lactate. Together, these cellular findings suggested an E4 associated increase in aerobic glycolysis (i.e. the Warburg effect). To test whether this phenomenon translated to APOE4 humans, we analyzed the plasma metabolome of young and middle-aged human participants with and without the E4 allele, and used indirect calorimetry to measure whole body oxygen consumption and energy expenditure. In line with data from E4-expressing mice, young female E4 carriers showed a striking decrease in energy expenditure compared to non-carriers. This decrease in energy expenditure was primarily driven by a lower rate of oxygen consumption, and was exaggerated following a dietary glucose challenge. Further, the stunted oxygen consumption was accompanied by markedly increased lactate in the plasma of E4 carriers, and a pathway analysis of the plasma metabolome suggested an increase in aerobic glycolysis. Together, these results suggest astrocyte, brain and system-level metabolic reprogramming in the presence of APOE4, a Warburg like endophenotype that is observable in young humans decades prior to clinically manifest AD. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.08.331025v1?rss=1 Authors: Clarke, H. J., Messaritaki, E., Dimitriadis, S. I., Metzler-Baddeley, C. Abstract: Background: Alzheimer's Disease (AD) is the most common form of dementia with genetic and environmental risk contributing to its development. Graph theoretical analyses of brain networks constructed from structural and functional MRI measurements have identified connectivity changes in AD and individuals with mild cognitive impairment (MCI). However, brain connectivity in asymptomatic individuals at risk of AD remains poorly understood. Methods: We acquired diffusion-weighted magnetic resonance imaging (dMRI) data from 165 asymptomatic individuals (38-71 years) from the Cardiff Ageing and Risk of Dementia Study (CARDS). We calculated white matter tracts and constructed whole-brain, default-mode-network and visual structural brain networks that incorporate multiple structural metrics as edge weights. We then calculated the relationship of three AD risk factors, namely Apolipoprotein-E {varepsilon}4 genotype (APOE4), family history (FH) of dementia, and central obesity, on graph theoretical measures and hubs. Results: We observed no risk-related differences in clustering coefficients, characteristic path lengths, eccentricity, diameter and radius across the whole-brain, default-mode-network or visual system. However, a hub in the right paracentral lobule was present in all high-risk groups (FH, APOE4, obese) but absent in low-risk groups (no FH, APOE4-ve, healthy weight). Discussion: We identified no risk-related effects on graph theoretical metrics in the structural brain networks of cognitively healthy individuals. However, high-risk was associated with a hub in the right paracentral lobule, an area with motor and sensory functions related to the lower limb. If this phenotype is shown to predict symptom development in longitudinal studies, it could be used as an early biomarker of AD. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.20.258749v1?rss=1 Authors: Wang, Y., Lian, M., Song, L., Wu, S. Abstract: Metabolism of beta-amyloid is critical for healthy brain. Decreased clearance of beta-amyloid is associated with ensued accumulation of amyloid peptide, culminating in formation of senile plaques, a neuropathological hallmark of Alzheimer disease(AD). Apolipoprotein E (APOE), a lipoprotein for phospholipid and cholesterol metabolism, is predominantly synthesized by glia in the central nervous system, controlling A-beta; aggregation and metabolism. By use of stereotactic injection and a Morris water maze, we found that delivery of Dicer1-expressing adenovirus into the hippocampus of an animal model of AD mice APPswe/PSEN1deltaE9 significantly improved spatial memory. The effect was associated with reduced amyloid peptides in the hippocampus which were analyzed with immunofluorescence and enzyme-linked immunosorbent assay. With western blot, quantitative real-time PCR, fluorescence in situ hybridization, and northern blot, Dicer1 overexpression increased apolipoprotein E (APOE) and concomitantly decreased B2 RNA in the hippocampus of the AD mice and in astrocyte cultures whereas transfection of B2 Mm2 RNA decreased APOE mRNA and protein levels in astrocyte cultures. Further,human or mouse APOE mRNA was found containing Alu RNA or its equivalent, B2 Mm2 RNA,locating downstream of its 3-untranslated region (UTR), respectively. The 3-UTR or 3-UTR in conjunction with the downstream Alu/B2 RNA were cloned into a luciferase reporter; with dual-luciferase assay, we found that simultaneous transfection of Dicer1 siRNA or Alu/B2 RNA decreased the corresponding luciferase activities which suggest that Alu RNA mediated APOE mRNA degradation. Altogether, Dicer1 expression mediated amyloid peptide clearance by increasing APOE via blocking B2 RNA-mediated APOE mRNA degradation. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.18.255299v1?rss=1 Authors: Prakashchand, D. D., Mondal, J. Abstract: Apolipoprotein E ( ApoE) is a major determinant protein of lipid-metabolism and actively participates in lipid transport in plasma and central nervous system. As a part of its lipid-transport activity, low-density-lipid receptor (LDLR) needs to recognise apoE as a ligand. But, all prior evidences point to the fact that the recognition of apoE by LDLR only takes place in presence of lipid molecules which are assumed to play an important role in conformationally activating apoE upon binding. However, the molecular mechanism underlying the complexation process of apoE with lipid molecules and associated lipid-induced conformational change of apoE are currently elusive. Here we capture the spontaneous complexation process of monomeric apoE3 and phospholipid molecules by employing molecular dynamics simulation at multiple resolution. In particular, our multi scale simulations demonstrate a large-scale conformational change of the full-length apoE3, triggered by two-stage apoE-lipid complexation process. At first stage, lipid molecules assemble close to C-terminal domain of the protein and induce a rapid separation of C-terminal domain of monomeric apoE3 from rest of its tertiary fold. In the second and final stage, long-time scale simulation captures a slow on-the-fly lipid-induced inter-helix separation process in N-terminal domain of the protein. The resultant equilibrated complex, as obtained in the current work resembles an `open conformation' of lipid-stabilised apoE, previously hypothesised based on small-angle X-ray scattering experiments. Taken together, the simulations provide a molecular view of kinetic interplay of apoE and lipid complexation multi-stage process leading to conformational changes in protein, potentially making it conducive for recognising LDLR. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.15.201723v1?rss=1 Authors: La Cunza, N., Tan, L. X., Rathnasamy, G., Thamban, T., Germer, C. J., Toops, K. A., Lakkaraju, A. Abstract: The retinal pigment epithelium (RPE) is the site of initial damage leading to photoreceptor degeneration and vision loss in age-related macular degeneration (AMD). Genetic and histopathological studies implicate cholesterol dysregulation in AMD; yet mechanisms linking cholesterol to RPE injury and drusen formation remain poorly understood. Especially enigmatic are allelic variants of the cholesterol transporter APOE, major risk modifiers in Alzheimer's disease that show reversed risk associations with AMD. Here, we investigated how ApoE isoforms modulate RPE health using live-cell imaging of primary RPE cultures and high-resolution imaging of human donor tissue. We show that the AMD-protective ApoE4 efficiently transports cholesterol and safeguards RPE homeostasis despite cellular stress. In contrast, ApoE2-expressing RPE accumulate cholesterol, which promotes autophagic deficits and complement-mediated mitochondrial fragmentation. Redox-related order-disorder phase transitions in ApoE2 drive the formation of intracellular biomolecular condensates as potential drusen precursors. Drugs that restore mitochondrial function limit condensate formation in ApoE2-RPE. Autophagic and mitochondrial defects correlate with intracellular ApoE aggregates in AMD donor RPE. Our study elucidates how AMD risk variants act as tipping points to divert the RPE from normal aging towards AMD by disrupting critical metabolic functions, and identifies mitochondrial stress-mediated aberrant phase transitions as a novel mechanism of drusen biogenesis. Copy rights belong to original authors. Visit the link for more info
Interview with Michael L Lipton, MD, author of Associations of Apolipoprotein E ε4 Genotype and Ball Heading With Verbal Memory in Amateur Soccer Players
Interview with Michael L Lipton, MD, author of Associations of Apolipoprotein E ε4 Genotype and Ball Heading With Verbal Memory in Amateur Soccer Players
Interview with Keith A. Josephs, MD, MST, MSc, author of Association of Apolipoprotein E ε4 With Transactive Response DNA-Binding Protein 43
Interview with Keith A. Josephs, MD, MST, MSc, author of Association of Apolipoprotein E ε4 With Transactive Response DNA-Binding Protein 43
Interview with Arthur W. Toga, PhD, author of Apolipoprotein E Genotype and Sex Risk Factors for Alzheimer Disease: A Meta-Analysis, and Dena Dubal, MD, PhD, author of Apolipoprotein E ε4 and Risk Factors for Alzheimer Disease—Let’s Talk About Sex
Multiple Sclerosis Discovery: The Podcast of the MS Discovery Forum
[intro music] Host – Dan Keller Hello, and welcome to Episode Thirty-Two of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller. This week’s podcast features an interview with Dr. David Holtzman of Washington University in St. Louis about how a protein implicated in Alzheimer’s disease may also have a role in MS progression. But to begin, here's a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org. We recently added a new data visualization to our growing collection. This one organizes every ongoing MS clinical trial—142 of them—into an interactive bubble chart. The size of each bubble represents the sample size of the trial, and the color indicates if the compound has been used to treat MS before. You can organize the chart 10 different ways, including by phase, compound, and sponsor. Go to the “Research Resources” section of our page and click on “data visualizations” to view it. Yet another Phase 2 trial on autologous hematopoietic stem cell transplant was published last week. We reported on this trial’s results and how it was different from previous trials we covered. Like the last two studies we reported on, this current study yielded very encouraging results. To view all of the stem cell stories, go to the “news and future directions” section of our website and look for any story with an image of a mouse in a little white lab coat. New research from the journal Neurology suggests that imaging measurements of the spinal cord and retina independently correlate to disability. Specifically, damage in the two structures was related to visual acuity and to the patient’s ability to discern vibration sensation. The authors suggested that clinicians may want to incorporate scans of the spinal cord and retina into their routine practice. [transition music] Now to the interview. Dr. David Holtzman is Chairman of the Department of Neurology at Washington University. He met with MSDF senior science journalist, Carol Cruzan Morton, at a recent Keystone meeting in Taos, New Mexico, to discuss how his work on apolipoprotein Ein Alzheimer's disease may be relevant to MS. Interviewee – David Holtzman Most of my career has been focused on trying to understand the pathogenesis of Alzheimer's disease, as well as to develop better diagnostic and treatment methods. However, in doing that – in trying to study the science behind that disease – I've also worked a lot on how normal brain function might be related to not only Alzheimer's disease but just some of the proteins that are involved in both Alzheimer's disease and related disorders. Interviewer – Carol Cruzan Morton We're at the Keystone meeting on neuroinflammation in Taos, New Mexico, and at the talk this morning you mentioned that there might be a connection between the ApoE and this protein involved in Alzheimer's and MS. Can you talk a little bit more about how that protein works normally in an Alzheimer's, and how you came to make that connection to multiple sclerosis? Dr. Holtzman Sure. Apolipoprotein E first just in terms of a risk factor for Alzheimer's disease ApoE is present as a protein in all of our bodies. It's made in the brain; it's made by the liver; it's at very high levels in the bloodstream. ApoE plays a role in the bloodstream in transporting lipids around the body. It turns out, though, that if the only thing it did was to transport lipids in the blood then you would probably only need to produce it in the liver so that it was secreted into the blood. But interestingly, it's also produced in several other organs: the ovary, the testes, the brain, and a few other places. So in those other organs, it doesn't probably have exactly the same function that it does when it's made by the liver. But the form of the lipoprotein that's in the brain that ApoE is within is somewhat different than it is, for example, in the bloodstream. It's in what's called HDL or high-density lipoproteins in the brain. MSDF That's a good thing, right? Dr. Holtzman That's the good cholesterol. That's the good cholesterol in the blood. In the brain, it's not entirely clear what these HDL lipoprotein particles are really doing. So, for example, if ApoE is absent from the brain of a person, and there are people that have genetic mutations, they have no ApoE in their body… MSDF Completely gone. Dr. Holtzman Completely gone. And they have developed serious problems with cholesterol buildup in their arteries because they can't clear big lipoprotein particles from their blood, but their brain is okay, no problem. The people are born normal; brain is okay. And there are probably other proteins in the brain that may be able to takeover for its function in the brain; whereas in the blood that's not the case. MSDF And when it goes wrong in Alzheimer's, what's happening…? Dr. Holtzman So that's a different issue. So in Alzheimer's disease, there's no lack of ApoE. In humans, there's three different flavors of ApoE: ApoE2, ApoE3, or ApoE4. And there's a very, very subtle difference between the ApoE2, 3, and 4; just really, really small difference. So brain function in people that are of different ApoE types is normal when they're born and when they grow up and as adults. But for some reason – which we'll talk about in a moment – when people have the ApoE4 form of ApoE, it causes a higher risk for Alzheimer's disease probably because it's promoting the buildup of one of the proteins that's really important in causing Alzheimer's disease earlier. So this amyloid protein that builds up in Alzheimer's is strongly influenced by the form of ApoE that you produce. So if you make the E4 form, it's probably because amyloid doesn't get cleared away as well; it builds up earlier. And if you have the ApoE2 form, which is protective against Alzheimer's disease, it pushes out the development of amyloid deposition until very old ages, if ever. That may be something that's related to Alzheimer's disease that's distinct from what it might do in other diseases of the brain like MS, for example. MSDF How did you make that connection to MS? Dr. Holtzman Right. So over the years, there's been a number of scientists and physicians around the world who have studied the many possible functions of ApoE in the body. And for gosh it's been about 30 years or so, there's been reports that one of the things that ApoE does is to influence inflammatory cells: T cells, macrophages, etc. MSDF All over the body or in the brain and spine? Dr. Holtzman Yeah, in different locations actually. It's never been completely clear exactly what ApoE is doing to the immune system. A lot of studies individually show effects, but it's not entirely clear what it's doing. And so, I got interested in this personally a few years ago there was a prominent paper published suggesting that one of the things that ApoE does to the immune system outside the brain is to help present antigens to the immune system if they contain lipids. And so, that caught my attention because, one, ApoE carries lipids. And just naively I thought well if it helps present lipid antigens in multiple sclerosis the antigens that are being attacked generally are the lipid related antigens. MSDF The myelin. Dr. Holtzman The myelin, right, exactly. So I thought well that seems, you know, maybe there's something to this that one could study in relation to MS because of that. MSDF And then how did you go about asking those question? Where did you start? Dr. Holtzman Basically, I thought alright, well a lot of people who work on MS if they use animal studies use the model EAE. So we thought well some of my colleagues at Washington University have been using the EAE model for years – like many people have – and so we thought well the obvious experiment to try first is just compare animals that express ApoE in their body versus those that don't. And simply ask the question is there anything different about EAE in an animal that lacks ApoE or not? And so, first, we started working with Anne Cross and then later with Greg Wu together who are experts in using animal models of MS. And ultimately published findings showing – and a few other groups have worked on this, as well – showing that there appears to be decreased clinical severity of EAE in a slightly later onset of disease in animals that lack ApoE. MSDF And what does that tell you…there might be a role or…? Dr. Holtzman Obviously many other studies would need to be done to know if it has a role in human MS. But once we found that, particularly Greg's lab began to ask the question well if that's true what's the mechanism? If there is a mechanism that we could hone in on, is that something that seems logical based on what we actually know about ApoE already? And so, the things that kind of came out of our first series of studies was that – unlike what I initially had thought from this earlier paper – it doesn't appear that ApoE is modifying antigen presentation of cells or the ability of T cells to react against the brain. But something once T cells do get in the brain to attack myelin and other components, there's something about that ApoE is acting on at that point. It could be that it's involved in allowing the myelin to repair, or alternatively it could be that when T cells get into the brain and interact with other cells in the brain – like other immune cells like microglial cells or dendritic cells – that that interaction is altered by ApoE within the brain. That might make sense given that ApoE is highly expressed by macrophages outside the brain, and inside the brain it's highly expressed by what are called activated microglial cells. So kind of the macrophages of the brain. So that's where we kind of are now, and I think there's a lot more studies that could be done to really understand both that interaction as well as whether human ApoE causes the same effect that we saw in animals as mouse ApoE. Because they're not exactly the same; they're similar but not the same. MSDF Is there other evidence connecting ApoE or its various forms with MS? Dr. Holtzman There are human studies that have been done trying to ask the very simple questions of is the ApoE4, which is a risk factor for Alzheimer's, is that over represented in MS? Or is the ApoE2 form, which is under represented in Alzheimer's, is that protective against MS? And the studies on this some have suggested effects, some haven't. There's no clear answer. But I think if ApoE is involved in MS, it would be less likely to be involved in whether you get MS but more likely involved in the progression of the disease. And I know in the MS field one of the big areas now – now that there's so many studies and as well as treatments that have emerged that are quite effective at suppressing the initial phases of MS, the immune response phases – a lot the work is going into understanding this prolonged progressive phase of MS. And that's where ApoE could be important in sort of the repair and recovery of neurons and axons, for example. Because the fact it transports lipids between cells, maybe it has something to do with recovery of the brain after injury. And that's been speculated on for some time, although not as much work on that has been done in MS. MSDF Has it been speculated on in MS or MS and Alzheimer's both or…? Dr. Holtzman No, it's been speculated on after a variety of different brain injuries that it plays a role in redistributing lipids in the brain after injury, and that might be promoting recovery. So one possibility that still hasn't really been tested that I'm aware of in models of MS or in human MS is to whether that really happens for ApoE in the human brain or animal models. MSDF Can that be tested now? Dr. Holtzman Absolutely, absolutely. Those are some of the studies that I think are really critical as the next step. MSDF Is it conceivable that the body of knowledge for Alzheimer's research on ApoE might yield a treatment for progressive MS? Dr. Holtzman It's possible. I mean a lot of the understanding of what ApoE might be doing in the brain has really expanded because people have been studying Alzheimer's disease and its relationship with ApoE. So I can't imagine it wouldn't help with that because we've learned a lot so far. MSDF Are there other treatments in the pipeline for Alzheimer's related to ApoE? Dr. Holtzman There are. There's not too many things yet that have reached human trials, but there are groups trying to alter the level of ApoE in the brain or to alter its receptors in the brain as potential treatments for affecting Alzheimer's disease. So yeah, I mean those are the kind of things, as they advance, depending on what's found in regard to the relationship between ApoE and MS could be tried in MS. I don't see why not. MSDF That's interesting. What else should I be asking? Dr. Holtzman I think what scientifically what I think is really important to still sort out in this area is that when the innate immune cells of the brain – the microglial cells or even macrophages when they get into the brain – they produce tremendous levels of ApoE when that happens. And I think understanding what that protein is really doing in that setting could provide insight into future treatments. So that's what I think is really fascinating to try to understand. MSDF Well if it happens in Alzheimer's, as well, it happens before the blood-brain barrier breaks down and then after it, it sounds like. Dr. Holtzman Well, in MS, it's probably occurring after there's cell entry into the brain. But the upregulation of ApoE by these innate immune cells is much higher in MS than it is in Alzheimer's disease. MSDF Oh, is that right? Dr. Holtzman Yeah, yeah. MSDF That's interesting. That's even more interesting. Dr. Holtzman Yeah, I know. That's why it's really, really fascinating. I think one of the figures from the paper that we published last year from Greg's lab showed that the level of ApoE increasing in microglial cells versus similar cells that are present in the spleen of an animal is like 25 times higher in the setting of an EAE model than normal. So it's really, really high. Is it really doing anything, or is it just a byproduct? I suspect it probably is doing something. So that's what I think would be really interesting to figure out. MSDF Thanks. Well I appreciate your taking time out at the Keystone meeting to talk with MS Discovery Forum. Dr. Holtzman Yeah, it's great. Well good luck. MS is such a…the treatments that have been evolving are so exciting compared to Alzheimer's disease where we don't yet have good treatments. So I think there will be soon, but I think it's a great opportunity to even advance for ... MSDF Is there a chance that the reverse could be true? That treatments existing for MS would be helpful in Alzheimer's? Dr. Holtzman That's a good question. I don't know if any of the frequently used ones where you're preventing cell entry into the brain necessarily would be useful for Alzheimer's. But like one of the new drugs, Tecfidera, this oral medication does do some interesting things to cells in the brain that might be useful in a disease like Alzheimer's. So maybe there will be some things that we can translate. MSDF I appreciate it. Thank you so much. Dr. Holtzman Thank you. [transition music] Thank you for listening to Episode Thirty-Two of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations. Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances. We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org. [outro music]
Interview with Richard Mayeux, MD, MSc, author of Variants in the ATP-Binding Cassette Transporter (ABCA7), Apolipoprotein E ε4, and the Risk of Late-Onset Alzheimer Disease in African Americans
Interview with Eric M. Reiman, MD and Hillary D. Protas, PhD, authors of Posterior Cingulate Glucose Metabolism, Hippocampal Glucose Metabolism, and Hippocampal Volume in Cognitively Normal, Late-Middle-Aged Persons at 3 Levels of Genetic Risk for Alzheimer Disease, and William Jagust, MD, author of Apolipoprotein E, Neurodegeneration, and Alzheimer Disease
Inhibition of Apolipoprotein-E signaling is a potential clinical strategy for enhancing the delivery of neuroprotective drugs to the brain after ischemic stroke.
Sat, 1 Jan 1983 12:00:00 +0100 https://epub.ub.uni-muenchen.de/6482/1/6482.pdf Schwandt, P.; Jüngst, Dieter; Weisweiler, P. ddc:610, Medizin