Skip to main content
Key Specialties
Anesthesiology Cardiology Dermatology Diabetology Endocrinology Gastroenterology General Medicine Geriatrics Hematology Infectious Diseases Internal Medicine Nephrology Neurology Obstetrics and Gynecology Oncology Pediatrics Psychiatry Radiology Respiratory Medicine Rheumatology Surgery Urology
Congress Coverage
2024 ESMO Congress 2024 ERS Congress 2024 EASD Congress 2024 ESC Congress 2024 EAN Congress 2024 ASCO Annual Meeting 2024 ACC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote series | Spotlight on menopause

Menopause can have a significant impact on the body, with effects ranging beyond the endocrine and reproductive systems. Learn about the systemic effects of menopause, so you can help patients in your clinics through the transition.

Launching: Thursday 12th December 2024
ADVANCED SEARCH
Log in
Top
Molecular Neurodegeneration
Published in:

Open Access 01-12-2024 | Research article

Contribution of amyloid deposition from oligodendrocytes in a mouse model of Alzheimer’s disease

Authors: Akihiro Ishii, Joseph A. Pathoulas, Omar MoustafaFathy Omar, Yingying Ge, Annie Y. Yao, Tressa Pantalena, Neeraj Singh, John Zhou, Wanxia He, Patrick Murphy, Riqiang Yan, Xiangyou Hu

Published in: Molecular Neurodegeneration | Issue 1/2024

Login to get access

Abstract

Background

The accumulation of β-amyloid (Aβ) peptides into insoluble plaques is an early pathological feature of Alzheimer’s disease (AD). BACE1 is the sole β-secretase for Aβ generation, making it an attractive therapeutic target for AD therapy. While BACE1 inhibitors have been shown to reduce Aβ levels in people with AD, clinical trials targeting BACE1 have failed due to unwanted synaptic deficits. Understanding the physiological role of BACE1 in individual cell types is essential for developing effective BACE inhibitors for the treatment of AD. Recent single-cell RNA transcriptomic assays revealed that oligodendrocytes are enriched with genes required for generating Aβ. However, the contribution of oligodendrocytes to amyloid plaque burden in AD and the side effects of oligodendrocyte-specific Bace1 deletion remain to be explored.

Methods

We generated an oligodendrocyte-specific Bace1 knockout model (Bace1fl/fl;Olig2-Cre) to monitor potential disruptions in myelination using standard electron microscopy. Long-term potentiation (LTP) was monitored to measure synaptic integrity. We crossed the Bace1fl/fl;Olig2-Cre model with heterozygous AppNL−G−F/wt knock-in AD mice to generate AD mice lacking oligodendrocyte Bace1 (Bace1fl/fl;Olig2-Cre; AppNL−G−F/wt) and examined amyloid plaque number and insoluble Aβ levels and gliosis in these animals. Single nuclei RNA sequencing experiments were conducted to examine molecular changes in response to Bace1 deficiency in oligodendrocytes in the wild type or APP knock-in background.

Results

Bace1 deletion in oligodendrocytes caused no change in myelin thickness in the corpus callosum but a marginal reduction in myelin sheath thickness of the optic nerve. Synaptic strength measured by LTP was not different between Bace1fl/fl;Olig2-Cre and age-matched Bace1fl/fl control animals, suggesting no major effect on synaptic plasticity. Intriguingly, deletion of Bace1 in 12-month-old heterozygous AD knock-in mice (Bace1fl/fl;Olig2-Cre; AppNL−G−F/wt mice) caused a significant reduction of amyloid plaques by ~ 33% in the hippocampus and ~ 29% in the cortex compared to age-matched AD mice (Bace1fl/fl;AppNL−G−F/wt). Insoluble Aβ1–40 and Aβ1–42 levels were reduced comparably while more astrocytes and microglia were observed in surrounding amyloid plaques. Unbiased single-nuclei RNA sequencing results revealed that deletion of oligodendrocyte Bace1 in APPNL−G−F/wt knock-in mice increased expression of genes associated with Aβ generation and clearance such as ADAM10, Ano4, ApoE, Il33, and Sort1.

Conclusion

Our results provide compelling evidence that the amyloidogenic pathway in oligodendrocytes contributes to Aβ plaque formation in the AD brain. While specifically targeting BACE1 inhibition in oligodendrocytes for reducing Aβ pathology in AD is likely challenging, this is a potentially explorable strategy in future studies.
Appendix
Available only for authorised users
Literature
1.
Aarsland D, Creese B, Politis M, Chaudhuri KR, Ffytche DH, Weintraub D, Ballard C. Cognitive decline in Parkinson disease. Nat Rev Neurol. 2017;13:217–31.PubMedPubMedCentralCrossRef
2.
Bao H, Shen Y. Unmasking BACE1 in aging and age-related diseases. Trends Mol Med. 2023;29:99–111.PubMedCrossRef
3.
Baumann N, Pham-Dinh D. Biology of oligodendrocyte and myelin in the mammalian central nervous system. Physiol Rev. 2001;81:871–927.PubMedCrossRef
4.
Becht E, McInnes L, Healy J, Dutertre CA, Kwok IWH, Ng LG, Ginhoux F, Newell EW. Dimensionality reduction for visualizing single-cell data using UMAP. Nat Biotechnol; 2018.
5.
Benoit MR, Darboe M, Das B, Ge Y, Zhou J, Yao A, He W, Yan R, Hu X. Postnatal neuronal Bace1 deletion impairs neuroblast and oligodendrocyte maturation. Hum Mol Genet. 2023;32:1193–207.PubMedCrossRef
6.
Blanchard JW, Akay LA, Davila-Velderrain J, von Maydell D, Mathys H, Davidson SM, Effenberger A, Chen CY, Maner-Smith K, Hajjar I, et al. APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes. Nature. 2022;611:769–79.PubMedPubMedCentralCrossRef
7.
Bosseboeuf E, Raimondi C. (2020). Signalling, Metabolic Pathways and Iron Homeostasis in Endothelial Cells in Health, Atherosclerosis and Alzheimer’s Disease. Cells 9.
8.
Chatila ZK, Kim E, Berlé C, Bylykbashi E, Rompala A, Oram MK, Gupta D, Kwak SS, Kim YH, Kim DY et al. (2018). BACE1 Regulates Proliferation and Neuronal Differentiation of Newborn Cells in the Adult Hippocampus in Mice. eNeuro 5.
9.
Das B, Singh N, Yao AY, Zhou J, He W, Hu X, Yan R. BACE1 controls synaptic function through modulating release of synaptic vesicles. Mol Psychiatry; 2021.
10.
11.
Depp C, Sun T, Sasmita AO, Spieth L, Berghoff SA, Nazarenko T, Overhoff K, Steixner-Kumar AA, Subramanian S, Arinrad S, et al. Myelin dysfunction drives amyloid-β deposition in models of Alzheimer’s disease. Nature. 2023;618:349–57.PubMedPubMedCentralCrossRef
12.
Desai MK, Guercio BJ, Narrow WC, Bowers WJ. An Alzheimer’s disease-relevant presenilin-1 mutation augments amyloid-beta-induced oligodendrocyte dysfunction. Glia. 2011;59:627–40.PubMedPubMedCentralCrossRef
13.
Egan MF, Mukai Y, Voss T, Kost J, Stone J, Furtek C, Mahoney E, Cummings JL, Tariot PN, Aisen PS, et al. Further analyses of the safety of verubecestat in the phase 3 EPOCH trial of mild-to-moderate Alzheimer’s disease. Alzheimers Res Ther. 2019;11:68.PubMedPubMedCentralCrossRef
14.
15.
Fernández-Calle R, Konings SC, Frontiñán-Rubio J, García-Revilla J, Camprubí-Ferrer L, Svensson M, Martinson I, Boza-Serrano A, Venero JL, Nielsen HM, et al. APOE in the bullseye of neurodegenerative diseases: impact of the APOE genotype in Alzheimer’s disease pathology and brain diseases. Mol Neurodegener. 2022;17:62.PubMedPubMedCentralCrossRef
16.
Fleck D, Garratt AN, Haass C, Willem M. BACE1 dependent neuregulin processing: review. Curr Alzheimer Res. 2012;9:178–83.PubMedCrossRef
17.
Fu AK, Hung KW, Yuen MY, Zhou X, Mak DS, Chan IC, Cheung TH, Zhang B, Fu WY, Liew FY, et al. IL-33 ameliorates Alzheimer’s disease-like pathology and cognitive decline. Proc Natl Acad Sci U S A. 2016;113:E2705–2713.PubMedPubMedCentralCrossRef
18.
Furusho M, Dupree JL, Nave KA, Bansal R. Fibroblast growth factor receptor signaling in oligodendrocytes regulates myelin sheath thickness. J Neurosci. 2012;32:6631–41.PubMedPubMedCentralCrossRef
19.
Hampel H, Vassar R, De Strooper B, Hardy J, Willem M, Singh N, Zhou J, Yan R, Vanmechelen E, De Vos A, et al. The β-Secretase BACE1 in Alzheimer’s Disease. Biol Psychiatry; 2020.
20.
Hao Y, Hao S, Andersen-Nissen E, Mauck WM 3rd, Zheng S, Butler A, Lee MJ, Wilk AJ, Darby C, Zager M, et al. Integrated analysis of multimodal single-cell data. Cell. 2021;184:3573–87. e3529.PubMedPubMedCentralCrossRef
21.
Hartlage-Rübsamen M, Zeitschel U, Apelt J, Gärtner U, Franke H, Stahl T, Günther A, Schliebs R, Penkowa M, Bigl V, et al. Astrocytic expression of the Alzheimer’s disease beta-secretase (BACE1) is stimulus-dependent. Glia. 2003;41:169–79.PubMedCrossRef
22.
Hu X, Das B, Hou H, He W, Yan R. BACE1 deletion in the adult mouse reverses preformed amyloid deposition and improves cognitive functions. J Exp Med. 2018;215:927–40.PubMedPubMedCentralCrossRef
23.
Hu X, Fan Q, Hou H, Yan R. Neurological dysfunctions associated with altered BACE1-dependent Neuregulin-1 signaling. J Neurochem. 2016;136:234–49.PubMedCrossRef
24.
Hu X, Hicks CW, He W, Wong P, Macklin WB, Trapp BD, Yan R. Bace1 modulates myelination in the central and peripheral nervous system. Nat Neurosci. 2006;9:1520–5.PubMedCrossRef
25.
Hu X, Shi Q, Zhou X, He W, Yi H, Yin X, Gearing M, Levey A, Yan R. Transgenic mice overexpressing reticulon 3 develop neuritic abnormalities. EMBO J. 2007;26:2755–67.PubMedPubMedCentralCrossRef
26.
Hussain I, Powell D, Howlett DR, Tew DG, Meek TD, Chapman C, Gloger IS, Murphy KE, Southan CD, Ryan DM, et al. Identification of a novel aspartic protease (asp 2) as beta-secretase. Mol Cell Neurosci. 1999;14:419–27.PubMedCrossRef
27.
Karran E, De Strooper B. The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics. Nat Rev Drug Discov. 2022;21:306–18.PubMedCrossRef
28.
Kenigsbuch M, Bost P, Halevi S, Chang Y, Chen S, Ma Q, Hajbi R, Schwikowski B, Bodenmiller B, Fu H, et al. A shared disease-associated oligodendrocyte signature among multiple CNS pathologies. Nat Neurosci. 2022;25:876–86.PubMedPubMedCentralCrossRef
29.
Korsunsky I, Millard N, Fan J, Slowikowski K, Zhang F, Wei K, Baglaenko Y, Brenner M, Loh PR, Raychaudhuri S. Fast, sensitive and accurate integration of single-cell data with Harmony. Nat Methods. 2019;16:1289–96.PubMedPubMedCentralCrossRef
30.
Leitzke S, Seidel J, Ahrens B, Schreiber R, Kunzelmann K, Sperrhacke M, Bhakdi S, Reiss K. (2022). Influence of Anoctamin-4 and – 9 on ADAM10 and ADAM17 sheddase function. Membranes (Basel) 12.
31.
Lim KH, Yang S, Kim SH, Joo JY. Identifying New COVID-19 receptor Neuropilin-1 in severe Alzheimer’s Disease patients Group Brain using genome-wide Association Study Approach. Front Genet. 2021;12:741175.PubMedPubMedCentralCrossRef
32.
Lombardo S, Chiacchiaretta M, Tarr A, Kim W, Cao T, Sigal G, Rosahl TW, Xia W, Haydon PG, Kennedy ME, et al. BACE1 partial deletion induces synaptic plasticity deficit in adult mice. Sci Rep. 2019;9:19877.PubMedPubMedCentralCrossRef
33.
Majercak J, Ray WJ, Espeseth A, Simon A, Shi XP, Wolffe C, Getty K, Marine S, Stec E, Ferrer M, et al. LRRTM3 promotes processing of amyloid-precursor protein by BACE1 and is a positional candidate gene for late-onset Alzheimer’s disease. Proc Natl Acad Sci U S A. 2006;103:17967–72.PubMedPubMedCentralCrossRef
34.
Martens YA, Zhao N, Liu CC, Kanekiyo T, Yang AJ, Goate AM, Holtzman DM, Bu G. ApoE Cascade Hypothesis in the pathogenesis of Alzheimer’s disease and related dementias. Neuron. 2022;110:1304–17.PubMedPubMedCentralCrossRef
35.
McDade E, Voytyuk I, Aisen P, Bateman RJ, Carrillo MC, De Strooper B, Haass C, Reiman EM, Sperling R, Tariot PN, et al. The case for low-level BACE1 inhibition for the prevention of Alzheimer disease. Nat Rev Neurol; 2021.
36.
Moura DMS, Brennan EJ, Brock R, Cocas LA. Neuron to Oligodendrocyte Precursor Cell synapses: protagonists in Oligodendrocyte Development and Myelination, and targets for therapeutics. Front Neurosci. 2021;15:779125.PubMedCrossRef
37.
Müller SA, Shmueli MD, Feng X, Tüshaus J, Schumacher N, Clark R, Smith BE, Chi A, Rose-John S, Kennedy ME, et al. The Alzheimer’s disease-linked protease BACE1 modulates neuronal IL-6 signaling through shedding of the receptor gp130. Mol Neurodegener. 2023;18:13.PubMedPubMedCentralCrossRef
38.
Nasrabady SE, Rizvi B, Goldman JE, Brickman AM. White matter changes in Alzheimer’s disease: a focus on myelin and oligodendrocytes. Acta Neuropathol Commun. 2018;6:22.PubMedPubMedCentralCrossRef
39.
Novak G, Streffer JR, Timmers M, Henley D, Brashear HR, Bogert J, Russu A, Janssens L, Tesseur I, Tritsmans L, et al. Long-term safety and tolerability of atabecestat (JNJ-54861911), an oral BACE1 inhibitor, in early Alzheimer’s disease spectrum patients: a randomized, double-blind, placebo-controlled study and a two-period extension study. Alzheimers Res Ther. 2020;12:58.PubMedPubMedCentralCrossRef
40.
Ou-Yang MH, Kurz JE, Nomura T, Popovic J, Rajapaksha TW, Dong H, Contractor A, Chetkovich DM, Tourtellotte WG, Vassar R. (2018). Axonal organization defects in the hippocampus of adult conditional BACE1 knockout mice. Science translational medicine 10.
41.
Pratsch K, Unemura C, Ito M, Lichtenthaler SF, Horiguchi N, Herms J. (2023). New highly selective BACE1 inhibitors and their effects on dendritic spine density in vivo. Int J Mol Sci 24.
42.
Rajani RM, Ellingford R, Hellmuth M, Harris SS, Taso OS, Graykowski D, Lam FKW, Arber C, Fertan E, Danial JSH, et al. Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer’s disease. PLoS Biol. 2024;22:e3002727.PubMedPubMedCentralCrossRef
43.
Raulin AC, Doss SV, Trottier ZA, Ikezu TC, Bu G, Liu CC. ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies. Mol Neurodegener. 2022;17:72.PubMedPubMedCentralCrossRef
44.
45.
Rossner S, Lange-Dohna C, Zeitschel U, Perez-Polo JR. Alzheimer’s disease beta-secretase BACE1 is not a neuron-specific enzyme. J Neurochem. 2005;92:226–34.PubMedCrossRef
46.
Ruan CS, Liu J, Yang M, Saadipour K, Zeng YQ, Liao H, Wang YJ, Bobrovskaya L, Zhou XF. Sortilin inhibits amyloid pathology by regulating non-specific degradation of APP. Exp Neurol. 2018;299:75–85.PubMedCrossRef
47.
Saito T, Matsuba Y, Mihira N, Takano J, Nilsson P, Itohara S, Iwata N, Saido TC. Single app knock-in mouse models of Alzheimer’s disease. Nat Neurosci. 2014;17:661–3.PubMedCrossRef
48.
Sasmita AO, Depp C, Nazarenko T, Sun T, Siems SB, Ong EC, Nkeh YB, Böhler C, Yu X, Bues B, et al. Oligodendrocytes produce amyloid-β and contribute to plaque formation alongside neurons in Alzheimer’s disease model mice. Nat Neurosci; 2024.
49.
50.
Sharoar MG, Palko S, Ge Y, Saido TC, Yan R. Accumulation of saposin in dystrophic neurites is linked to impaired lysosomal functions in Alzheimer’s disease brains. Mol Neurodegener. 2021;16:45.PubMedPubMedCentralCrossRef
51.
Singh N, Benoit MR, Zhou J, Das B, Davila-Velderrain J, Kellis M, Tsai LH, Hu X, Yan R. BACE-1 inhibition facilitates the transition from homeostatic microglia to DAM-1. Sci Adv. 2022a;8:eabo1286.PubMedPubMedCentralCrossRef
52.
Singh N, Das B, Zhou J, Hu X, Yan R. (2022). Targeted BACE-1 inhibition in microglia enhances amyloid clearance and improved cognitive performance. Sci Adv 8, eabo3610.
53.
Sinha S, Anderson JP, Barbour R, Basi GS, Caccavello R, Davis D, Doan M, Dovey HF, Frigon N, Hong J, et al. Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature. 1999;402:537–40.PubMedCrossRef
54.
Taylor HA, Przemylska L, Clavane EM, Meakin PJ. (2022). BACE1: more than just a β-secretase. Obes Rev 23, e13430.
55.
Vanzulli I, Papanikolaou M, De-La-Rocha IC, Pieropan F, Rivera AD, Gomez-Nicola D, Verkhratsky A, Rodríguez JJ, Butt AM. Disruption of oligodendrocyte progenitor cells is an early sign of pathology in the triple transgenic mouse model of Alzheimer’s disease. Neurobiol Aging. 2020;94:130–9.PubMedPubMedCentralCrossRef
56.
Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, et al. Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science. 1999;286:735–41.PubMedCrossRef
57.
Wang H, Song L, Laird F, Wong PC, Lee HK. BACE1 knock-outs display deficits in activity-dependent potentiation of synaptic transmission at mossy fiber to CA3 synapses in the hippocampus. J Neurosci. 2008;28:8677–81.PubMedPubMedCentralCrossRef
58.
Wang M, Song WM, Ming C, Wang Q, Zhou X, Xu P, Krek A, Yoon Y, Ho L, Orr ME, et al. Guidelines for bioinformatics of single-cell sequencing data analysis in Alzheimer’s disease: review, recommendation, implementation and application. Mol Neurodegener. 2022a;17:17.PubMedPubMedCentralCrossRef
59.
Wang N, Wang M, Jeevaratnam S, Rosenberg C, Ikezu TC, Shue F, Doss SV, Alnobani A, Martens YA, Wren M, et al. Opposing effects of apoE2 and apoE4 on microglial activation and lipid metabolism in response to demyelination. Mol Neurodegener. 2022b;17:75.PubMedPubMedCentralCrossRef
60.
Willem M, Garratt AN, Novak B, Citron M, Kaufmann S, Rittger A, DeStrooper B, Saftig P, Birchmeier C, Haass C. Control of peripheral nerve myelination by the beta-secretase BACE1. Science. 2006;314:664–6.PubMedCrossRef
61.
Wilson DM 3rd, Cookson MR, Van Den Bosch L, Zetterberg H, Holtzman DM, Dewachter I. Hallmarks of neurodegenerative diseases. Cell. 2023;186:693–714.PubMedCrossRef
62.
Wu T, Hu E, Xu S, Chen M, Guo P, Dai Z, Feng T, Zhou L, Tang W, Zhan L, et al. clusterProfiler 4.0: a universal enrichment tool for interpreting omics data. Innov (Camb). 2021;2:100141.
63.
Yan R, Bienkowski MJ, Shuck ME, Miao H, Tory MC, Pauley AM, Brashier JR, Stratman NC, Mathews WR, Buhl AE, et al. Membrane-anchored aspartyl protease with Alzheimer’s disease beta-secretase activity. Nature. 1999;402:533–7.PubMedCrossRef
64.
Young-Pearse TL, Lee H, Hsieh YC, Chou V, Selkoe DJ. Moving beyond amyloid and tau to capture the biological heterogeneity of Alzheimer’s disease. Trends Neurosci; 2023.
65.
Zawadzka M, Rivers LE, Fancy SP, Zhao C, Tripathi R, Jamen F, Young K, Goncharevich A, Pohl H, Rizzi M, et al. CNS-resident glial progenitor/stem cells produce Schwann cells as well as oligodendrocytes during repair of CNS demyelination. Cell Stem Cell. 2010;6:578–90.PubMedCrossRef
66.
Zheng GX, Terry JM, Belgrader P, Ryvkin P, Bent ZW, Wilson R, Ziraldo SB, Wheeler TD, McDermott GP, Zhu J, et al. Massively parallel digital transcriptional profiling of single cells. Nat Commun. 2017;8:14049.PubMedPubMedCentralCrossRef
67.
Zhou J, Singh N, Galske J, Hudobenko J, Hu X, Yan R. BACE1 regulates expression of Clusterin in astrocytes for enhancing clearance of β-amyloid peptides. Mol Neurodegener. 2023;18:31.PubMedPubMedCentralCrossRef
68.
Zhu K, Peters F, Filser S, Herms J. Consequences of pharmacological BACE inhibition on synaptic structure and function. Biol Psychiatry. 2018;84:478–87.PubMedCrossRef
Metadata
Title
Contribution of amyloid deposition from oligodendrocytes in a mouse model of Alzheimer’s disease
Authors
Akihiro Ishii
Joseph A. Pathoulas
Omar MoustafaFathy Omar
Yingying Ge
Annie Y. Yao
Tressa Pantalena
Neeraj Singh
John Zhou
Wanxia He
Patrick Murphy
Riqiang Yan
Xiangyou Hu
Publication date
01-12-2024
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2024
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/s13024-024-00759-z

Other articles of this Issue 1/2024

A partial Drp1 knockout improves autophagy flux independent of mitochondrial function

Nuclear pore and nucleocytoplasmic transport impairment in oxidative stress-induced neurodegeneration: relevance to molecular mechanisms in Pathogenesis of Parkinson’s and other related neurodegenerative diseases

  • Open Access
  • Review

APOE4 genotype and aging impair injury-induced microglial behavior in brain slices, including toward Aβ, through P2RY12

Alzheimer’s disease associated isoforms of human CD33 distinctively modulate microglial cell responses in 5XFAD mice

A perspective on Alzheimer’s disease: exploring the potential of terminal/paradoxical lucidity and psychedelics

Mitochondrial CISD1/Cisd accumulation blocks mitophagy and genetic or pharmacological inhibition rescues neurodegenerative phenotypes in Pink1/parkin models

Keynote series | Spotlight on menopause

Menopause can have a significant impact on the body, with effects ranging beyond the endocrine and reproductive systems. Learn about the broader systemic effects of menopause, so you can help patients in your clinics through the transition.

Launching: Thursday 12th December 2024
 

Prof. Martha Hickey
Dr. Claudia Barth
Dr. Samar El Khoudary
Developed by: Springer Medicine
Register your interest now

Advances in Alzheimer's

Alzheimer's research and care is changing rapidly. Keep up with the latest developments from key international conferences, together with expert insights on how to integrate these advances into practice.

This content is intended for healthcare professionals outside of the UK.

Supported by:
  • Lilly
Developed by: Springer Healthcare IME
Learn more
Image Credits