Henrietta NielsenSenior lecturer

TRANSLATIONAL NEURODEGENERATION GROUP

GROUP MEMBERS

Kalicharan Patra, Researcher
Veronica Cartocci, Postdoc
Daniel Twohig, PhD student
Andreas Giannisis, PhD student
Alenni Lopez Perez, master student
Carl Blomqvist, master student

ALUMNI
Jane Prihodova, master project student
Anna Edlund, PhD student
​Robert Forsyth, visiting student from Univresity of Illinois
Michael Prabhu, visiting student from University of Illinois
Melanie Schultz, Erasmus exchange student
Stephani Cabelnes, Erasmus exchange student
Anežka Niesnerova, lab technician
Dimitra Karampatsi, master project student
Andrés de la Rosa, master project student
Lur Agirrezabala Nieto, Erasmus exchange student
Joan Benedicto Gras, Erasmus exchange student
Nerea Capon, research trainee
Svenja Fiedler, research trainee
Natalia Fijol, research trainee
Catharina Lotsch, Erasmus exchange student
Durga Inturi, master diploma student
Erik Becher, research trainee
Simon Moussaud, researcher
Patricia Parra Martin, Erasmus exchange student
Kalicharan Patra, postdoc

RESEARCH FOCUS

Alzheimer’s disease (AD) followed by dementia with Lewy bodes is the main cause of neurodegenerative dementia. The neuropathological hallmarks for these disorders are different however they do share many similarities. Risk factors for both disorders include high age, gender and various environmental factors affected by diet, exercise and education. The APOEε4 allele is to date the strongest and most replicated genetic risk factor for sporadic late onset AD and recent studies have further demonstrated an increased risk of DLB in individuals carrying an APOEε4-allele. In contrary, the APOEε2 allele is protective against both disorders. In humans the APOE gene is polymorphic with 3 different variants (APOEε2, APOEε3, APOEε4) contrary to other mammals who only have one type. The biological mechanisms underlying the variation in risk of diseases due to APOE genotype are yet to be determined. It is well-known that individuals with an APOEε4 genotype exhibit AD-related brain pathology already at the 4th or 5th decade of life in the absence of cognitive symptoms. We have previously shown that the APOE gene product apolipoprotein E (apoE) negatively affects amyloid-β uptake in cultures of primary human glial cells (Nielsen et al 2010, Mulder et al 2014) as well as rodent cells (Fu et al 2016). Results from our recent studies also propose that APOEε4-carriers are deficient in plasma apoE due to a specific reduction of apoE4 isoform levels (Martinez-Morillo et al 2014). Whether this plasma apoE-deficiency contributes to risk of neurodegenerative disease is one of our main research areas.

In our group we investigate biological mechanisms promoting/leading to neurodegenerative dementia. Using primary human cell cultures we are investigating the cellular responses to disease-associated molecules and in brain tissues from patients with neurodegenerative dementia we are searching for disease-specific protein complexes that can be traced as biomarkers in either cerebrospinal fluid or plasma samples from patients at risk of or with neurodegenerative disease

Currently we are working on four main research topics:

1. Whether and how alpha-synuclein relates to Alzheimer’s disease pathogenesis and pathology
2. Whether and how the expression of different apoE variants in the periphery relates to pathological processes in the brain
3. Which plasma and cerebrospinal fluid markers can aid identification of individuals who will develop neurodegenerative disease and which markers can aid the differential diagnosis of patients with manifest neurodegenerative dementia
4. Identification of molecular mechanisms that drive insulin resistance and glucose hypometabolism in APOE4 carriers and patients with Alzheimer's disease

In our efforts to further our understanding of processes linked to neurodegenerative disease we have for several years closely collaborated with many international colleagues and are always open to new collaborations.

PUBLICATIONS

Original research papers

1. Patra K, Giannisis A, Edlund AK, Sando SB, Lauridsen C, Berge G, Grøntvedt GR, Bråthen G, White LR, Nielsen HM. Plasma Apolipoprotein E Monomer and Dimer Profile and Relevance to Alzheimer's Disease. 2019. Journal of Alzheimer's disease Sep 3. doi: 10.3233/JAD-190175.
2. Twohig D, Rodriguez-Vieitez E, Sando SB, Berge G, Lauridsen C, Møller I, Grøntvedt GR, Bråthen G, Patra K, Bu G, Benzinger TLS, Karch CM, Fagan A, Morris JC, Bateman RJ, Nordberg A, White LR, Nielsen HM. The relevance of cerebrospinal fluid α-synuclein levels to sporadic and familial Alzheimer’s disease. 2018. Accepted for publication in Acta Neuropathologica Communications 24-10-2018
3. Patra K, Soosaipillai A, Sando SB, Lauridsen C, Berge G, Møller I, Grøntvedt GR, Bråthen G, Begcevic I, Moussaud S, Minthon L, Hansson O, Diamandis EP, White LR, Nielsen HMN. Assessment of kallikrein 6 as a cross-sectional and longitudinal biomarker for Alzheimer's disease. 2018. Alzheimer’s Research & Therapy. Jan 29;10(1):9
4. Schultz N, Brännström K, Byman E, Moussaud S, Nielsen HMN, the Netherlands Brain Bank, Olofsson A, Wennström M. Amyloid-beta 1-40 is associated with alterations in NG2+ pericyte population ex vivo and in vitro. 2018. Aging Cell. Jun;17(3):e12728
5. Ogaki K, Martens YA, Heckman MG, Koga S, Walton RL, Soto-Ortolaza AI, Vargas E, Nielsen HMN, Fujioka S, Uitti RJ, Kanekiyo T, Wszolek ZK, Low PA, Singer W, Dickson DW, Bu G, Ross OA. Multiple system atrophy and apolipoprotein E. 2018. Movement Disorders Apr;33(4):647-650
6. Nielsen HM, Chen K, Lee W, Chen Y, Bauer RJ, 3rd, Reiman E, et al. Peripheral apoE isoform levels in cognitively normal APOE epsilon3/epsilon4 individuals are associated with regional gray matter volume and cerebral glucose metabolism. 2017. Alzheimer's Research & Therapy. Jan 30;9(1):5
7. Fu Y, Zhao J, Atagi Y, Nielsen HM, Liu CC, Zheng H, Shinohara M, Kanekiyo T, Bu G. Apolipoprotein E lipoprotein particles inhibit amyloid-β uptake through cell surface heparan sulphate proteoglycan. 2016. Molecular Neurodegeneration. May 5;11(1):37.
8. Wennström M, Surova Y, Hall S, Nilsson C, Minthon L, Hansson O, Nielsen HM. The Inflammatory Marker YKL-40 Is Elevated in Cerebrospinal Fluid from Patients with Alzheimer's but Not Parkinson's Disease or Dementia with Lewy Bodies. 2015. PLoS One. Aug 13;10(8):e0135458.
9. Hoozemans JJM, van Haastert ES, Mulder SD, Nielsen HM, Veerhuis R, Ruijtenbeek R, Rozemuller AJM, Hilhorts R, van der Vies SM. Increased IRAK-4 kinase activity in Alzheimer’s disease:  IRAK-1/4 inhibitor I prevents pro-inflammatory cytokine secretion but not uptake of amyloid beta by primary human glia. 2014. Journal of Clinical & Cellular Immunology. August 4: 5:4
10. Schultz N, Nielsen HM, Minthon L, Malin Wennström. Involvement of MMP-9 in Amyloid-beta 1-42 induced shedding of pericytic NG2. 2014. Journal of Neuropathology and Experimental Neurology.  Jul;73(7):684-92
11. Zhao J, Fu Y, Liu-C-C, Shinohara M, Nielsen HM, Dong Q, Kanekiyo T, Bu G. Retinoic acid isomers facilitate apolipoprotein E production and lipidation in astrocytes through the RXR/RAR pathway. 2014. Journal of Biological Chemistry. Apr 18;289(16):11282-92
12. Wennström M, Nielsen  HM,  Orhan F, Londos E, Minthon L, Erhardt S. Kynurenic acid levels in cerebrospinal fluid from patients with Alzheimer´s disease or dementia with Lewy bodies. 2014. International Journal of Tryptophan Research. 7: 1–7
13. Martinez-Morillo E, Hansson O, Atagi Y, Bu G, Minthon L, Diamandis EP, Nielsen HM. Total apolipoprotein E levels and specific isoform composition in cerebrospinal fluid and plasma from Alzheimer’s disease patients and controls. 2014. ACTA Neuropathologica. May;127(5):633-43
14. Martinez-Morillo E, Nielsen HM, Batruch I, Dabrovich AP, Begcevic I, Lopez MF, Minthon L, Bu G, Mattson N, Portelius E, Hansson O, Diamandis EP. Assessment of Peptide Chemical Modifications on the Development of an Accurate and Precise Multiplex Selected Reaction Monitoring Assay for Apolipoprotein E Isoforms. 2014. Journal of Proteome Research. Feb 7;13(2):1077
15. Mulder SD, Nielsen HM, Blankeinstein MA, Eikelenboom P, Veerhuis R. Apolipoproteins E and J interfere with amyloid-beta uptake by primary human astrocytes and microglia in vitro. 2014. GLIA Apr;62(4):493-503
16. Nielsen HM, Hall S, Surova Y, Nägga K, Nilsson C, Minthon L, Hansson O, Wennström M. Low levels of soluble NG2 in cerebrospinal fluid from patients with dementia with Lewy bodies. 2014. Journal of Alzheimer’s disease. Jan 1;40(2):343-50
17. Lindqvist D, Hall S, Surova S, Sporre O, Nielsen H, Janelidze S, Brundin L, Hansson O. Cerebrospinal fluid inflammatory markers in Parkinson´s disease - associations with depression, fatigue, and cognitive impairment. 2013. Brain, behavior, and immunity. Oct;33:183-9
18. Nielsen HM, Ek D, Avdic U, Orbjörn C, Hansson O,The Netherlands Brain Bank, Veerhuis R,
    Rozemuller AJM, Brun A, Minthon L, Wennström M. NG2 cells, a new trail for Alzheimer’s disease mechanisms? 2013. Acta Neuropathologica Communications May 9;1(1):7
19. Wennström M, Surova Y, Hall S, Nilsson C, Minthon L, Boström F, Hansson O, Nielsen HM. Low levels of neurosin and its substrate α-synuclein in patients with synucleinopathy. 2013. PLoS One. 2013;8(1):e53250. Epub 2013 Jan 8
20. Westin K, Buchave P, Nielsen HM, Minthon L, Janciauskiene S, Hansson O. High levels of CCL2 are associated with faster cognitive decline in prodromal Alzheimer’s disease. 2012. PLoS One. 2012;7(1):e30525. Epub 2012 Jan 30
21. Wennström M, Londos E, Minthon L, Nielsen HM. Altered CSF orexin and α-synuclein levels in dementia patients. 2012. Journal of Alzheimer’s Disease Jan 1;29(1):125-32.
22. Nielsen HM, Palmqvist S, Minthon L, Londos E, Wennström M. Gender-dependent levels of hyaluronic acid in cerebrospinal fluid of patients with neurodegenerative dementia. 2012. Current Alzheimer Research. Mar 1;9(3):257-66
23. Mulder SD, Veerhuis R, Blankenstein MA, Nielsen HM. The effect of amyloid associated proteins on the expression of genes involved in amyloid clearance by adult human astrocytes. 2012. Experimental Neurology Jan;233(1):373-9. Epub 2011 Nov 10
24. Nielsen HM, Mulder SD, Beliën JAM, Musters RJP, Eikelenboom P, Veerhuis R. Astrocytic Aβ1-42 uptake is determined by Aβ-aggregation state and the presence of amyloid-associated proteins. 2010. Glia. 58(10):1235-46.
25. Nielsen HM, Veerhuis R, Holmqvist B, Janciauskiene S. Binding and uptake of Abeta1-42 by primary human astrocytes in vitro. 2009. Glia 57(9):978-88
26. Trouw LA, Nielsen HM, Minthon L, Londos E, Landberg G, Veerhuis R, Janciauskiene S, Blom AM. C4b-binding protein in Alzheimer's disease: binding to Abeta1-42 and to dead cells. 2008. Molecular Immunology 45(13):3649-60
27. Nielsen HM, Minthon L, Londos E, Blennow K, Miranda E, Perez J, Crowther DC, Lomas DA, Janciauskiene SM. Plasma and CSF serpins in Alzheimer disease and dementia with Lewy bodies. 2007. Neurology 69(16):1569-1579
28. Nielsen HM, Londos E, Minthon L, Janciauskiene SM. Soluble adhesion molecules and angiotensin-converting enzyme in dementia. 2007. Neurobiology of Disease 26(1):27-35
29. Baker C, Nielsen HM, Minthon L, Wright HT, Chappell S, Okyere J, May S, Morgan K, Kalsheker N, Janciauskiene SM. 2007. Effects of Alzheimer's peptide and alpha1-antichymotrypsin on astrocyte gene expression. Neurobiology of Aging 28(1):51-61

Reviews

1. Twohig D, Nielsen HM. α-synuclein in the pathophysiology of Alzheimer's disease. 2019. Molecular Neurodegeneration Jun 11;14(1):23
2. Wennström M, Nielsen HM. Cell adhesion molecules in Alzheimer’s disease. 2012. Degenerative Neurological and Neuromuscular Disease. July 4;2012(2):65-77
3. Veerhuis R, Nielsen HM, Tenner AJ. Complement in the brain. 2011. Molecular Immunology 48(14):1592-603

Book chapters

1. Rodriguez-Vieitez E, Nielsen HM. Associations Between APOE Variants, Tau and α-Synuclein. Adv Exp Med Biol. 2019;1184:177-186. doi: 10.1007/978-981-32-9358-8_15

2. Carrasquillo MM, Bu G, Nielsen HM. 2012. Chapter 2: Apolipoprotein E. ‘Genetic Variants in Alzheimer's Disease’ edited by Carrasquillo and Morgan. Springer NY. June 30, 2013. ISBN 978-1-4614-7308-4

FUNDING

SELECTION OF TERMINATED GRANTS last 5 years

Marcus Borgströms Stiftelse (PI), 2015-2016

Alzheimer's Association New Investigator Grant (USA) (PI), 2015-2017

VINNMER/Marie Curie Fellowship Grant (PI), 2016-2018

Demensfonden (PI), 2017-2018

Åhlen-Stiftelsen (PI), 2017-2018

Marcus Borgströms Stiftelse (PI), 2017-2018

SCILIFE LAB Pilot Grant (PI), 2017-2018

ONGOING GRANT SUPPORT

Stiftelsen Olle Engkvist Byggmästare (PI), 2017-2019

Stiftelsen Olle Engkvist Byggmästare (PI), 2018-2020

Demensfonden (PI), 2019-2021

BrightFocus Foundation (USA) (PI), 2019-2022