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Research

Alzheimer’s disease

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Multiple Sclerosis

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Alzheimer’s disease

(contact: Herring/Keyvani)

Background

Alzheimer’s disease (AD) is a devastating neurodegenerative disease and the most common cause for dementia. For decades, amyloid beta (Aβ) and tau were considered as the key molecules in AD pathogenesis, therapy and diagnosis but intensive evaluation of these potential therapy targets was disillusioning in clinical trials. As treatment options are still very limited and with minor efficacy, novel disease-modifying, multimodal therapy targets are of immanent socioeconomic value for the aging societies of the world.

Research projects

Kallikrein-8 as a novel theranostic target in AD

The extracellular serine protease kallikrein-8 (KLK8, alias neuropsin) modulates cognitive functions by the processing of prominent neuroplasticity-related substrates. Our knowledge about the role of KLK8 in neuropathological processes is, however, very limited.

Our lab was the first to demonstrate dysregulated KLK8 signaling in diseased brains from both AD patients and transgenic mice. We found elevated cerebral levels of KLK8 mRNA and protein in the human brain in an early preclinical stage (CERAD A/Braak I-II) when only the first speck of Aβ deposition becomes apparent; in transgenic mouse, the up-regulation was detectable even prior to any Aβ deposition. Interestingly, cerebral KLK8 levels were, regardless of AD pathology, higher in women or female mice as compared to male individuals and in vitro experiments indicated that estrogen might be a trigger for this sex-specific KLK8 overproduction. KLK8 elevation is not only detectable in the brain but also in the blood and CSF of patients with early AD and even stronger with mild cognitive impairment (MCI). In this pilot cross-sectional study the diagnostic performance of CSF and blood KLK8 was relatively comparable and in the case of MCI, in part, even superior to that of the established CSF core biomarkers Aβ42, phospho-tau and total tau.

Intriguingly, we showed that both, short-term, antibody-mediated inhibition of pathologically elevated KLK8 as well as permanent, genetic KLK8 knockdown are capable of attenuating various pathologic features of AD in primary cells and transgenic mice in a sex-specific manner. Fortunately, in wildtype mice with normal physiological KLK8 levels, KLK8 inhibition or knockdown exhibited no or only slightly deteriorating effects on few parameters.

Together, these findings highlight KLK8 as a potential antecedent biomarker and therapeutic target in AD. Ongoing and future studies aim to validate the theranostic potential of KLK8 in order to translate KLK8 from bench to bedside.

Transgenerational effects of exercise on AD

A physically and mentally stimulating lifestyle tremendously reduces the risk of dementia and slows the cognitive decline in AD patients. First, it was assumed that training solely improves brain plasticity by increasing the cognitive reserve and thereby compensates functional deficits.

Experimental animal studies from our and other labs have though provided evidence that a stimulating environmental enrichment (EE) further interferes with the pathomechanisms of AD. Additionally, we demonstrated that EE exerts beneficial effects over a very extended period of ontogenesis, from in utero stimulation via maternal running during pregnancy until late exercise in a full-blown disease stage, and that the time point when enrichment starts determines the molecular mechanisms that conduct resistance to AD pathology.

Whether EE-induced protective effects against AD might even be transgenerationally inherited across several generations and if so, what epigenetic modifications enable maternal/paternal transmission are questions we currently aim to answer.

Funding: Deutsche Forschungsgemeinschaft (DFG), European Regional Development Fund (EFRE)

Selected Publications

  • Schramm S., Krizanovic N., Roggenbuck U., Jöckel KH., Herring A., Keyvani K., Jokisch M.. Blood Kallikrein-8 and Non-Amnestic Mild Cognitive Impairment: An Exploratory Study. J Alzheimers Dis Rep 3, 327-337. 10.3233/ADR-220073
  • Schramm S., Jokisch M., Jöckel KH., Herring A., Keyvani K.. Is kallikrein-8 a blood biomarker for detecting amnestic mild cognitive impairment? Results of the population-based Heinz Nixdorf Recall study. Alzheimers Res Ther 20, 202. 10.1186/s13195-021-00945-x
  • Herring A., Kurapati NK., Krebs S., Grammon N., Scholz LM., Voss G., Miah MR., Budny V., Mairinger F., Haase K., Teuber-Hanselmann S., Dobersalske C., Schramm S., Jöckel KH., Münster Y., Keyvani K. Genetic knockdown of Klk8 has sex-specific multi-targeted therapeutic effects on Alzheimer’s pathology in mice. Neuropathol Appl Neurobiol 47, 611-624. 10.1111/nan.12687
  • van Gerresheim EF., Herring A., Gremer L., Müller-Schiffmann A., Keyvani K., Korth C. The interaction of insoluble Amyloid-β with soluble Amyloid-β dimers decreases Amyloid-β plaque numbers. Neuropathol Appl Neurobiol 47, 603-610. 10.1111/nan.12685
  • Münster, Y., Keyvani, K. & Herring, A. Inhibition of excessive kallikrein-8 improves neuroplasticity in Alzheimer’s disease mouse model. Exp Neurol 324, 113115. 10.1016/j.expneurol.2019.113115
  • Teuber-Hanselmann, S., Rekowski, J., Vogelgsang, J., von Arnim, C., Reetz, K., Stang, A., Jöckel, K.H., Wiltfang, J., Esselmann, H., Otto, M., Tumani, H., Herring, A. & Keyvani, K. CSF and blood Kallikrein-8: a promising early biomarker for Alzheimer’s disease. J Neurol Neurosurg Psychiatry 91, 40-48. 10.1136/jnnp-2019-321073
  • Abdel-Hafiz, L., Müller-Schiffmann, A., Korth, C., Fazari, B., Chao, O.Y., Nikolaus, S., Schäble, S., Herring, A., Keyvani, K., Lamounier-Zepter, V., Huston, J.P. & de Souza Silva, M.A. Abeta dimers induce behavioral and neurochemical deficits of relevance to early Alzheimer’s disease. Neurobiol Aging 69, 1-9. 10.1016/j.neurobiolaging.2018.04.005
  • Keyvani, K., Münster, Y., Kurapati, N.K., Rubach, S., Schönborn, A., Kocakavuk, E., Karout, M., Hammesfahr, P., Wang, Y.C., Hermann, D.M., Teuber-Hanselmann, S. & Herring, A. Higher levels of kallikrein-8 in female brain may increase the risk for Alzheimer’s disease. Brain Pathol 28, 947-964. 10.1111/bpa.12599
  • Herring, A., Münster, Y., Akkaya, T., Moghaddam, S., Deinsberger, K., Meyer, J., Zahel, J., Sanchez-Mendoza, E., Wang, Y., Hermann, D.M., Arzberger, T., Teuber-Hanselmann, S. & Keyvani, K. Kallikrein-8 inhibition attenuates Alzheimer’s disease pathology in mice. Alzheimers Dement 12, 1273-1287. 10.1016/j.jalz.2016.05.006
  • Herring, A., Münster, Y., Metzdorf, J., Bolczek, B., Krüssel, S., Krieter, D., Yavuz, I., Karim, F., Roggendorf, C., Stang, A., Wang, Y., Hermann, D.M., Teuber-Hanselmann, S. & Keyvani, K. Late running is not too late against Alzheimer’s pathology. Neurobiol Dis 94, 44-54. 10.1016/j.nbd.2016.06.003
  • Müller-Schiffmann, A., Herring, A., Abdel-Hafiz, L., Chepkova, A.N., Schäble, S., Wedel, D., Horn, A.H., Sticht, H., de Souza Silva, M.A., Gottmann, K., Sergeeva, O.A., Huston, J.P., Keyvani, K. & Korth, C. Amyloid-beta dimers in the absence of plaque pathology impair learning and synaptic plasticity. Brain 139, 509-525. 10.1093/brain/awv355
  • Sankowski, R., Herring, A., Keyvani, K., Frenzel, K., Wu, J., Röskam, S., Noelker, C., Bacher, M. & Al-Abed, Y. The multi-target effects of CNI-1493: convergence of anti-amylodogenic and anti-inflammatory properties in animal models of Alzheimer’s disease. Mol Med 22, 776-788. 10.2119/molmed.2016.00163

  • Fritschi, S.K., Langer, F., Kaeser, S.A., Maia, L.F., Portelius, E., Pinotsi, D., Kaminski, C.F., Winkler, D.T., Maetzler, W., Keyvani, K., Spitzer, P., Wiltfang, J., Kaminski Schierle, G.S., Zetterberg, H., Staufenbiel, M. & Jucker, M. Highly potent soluble amyloid-beta seeds in human Alzheimer brain but not cerebrospinal fluid. Brain 137, 2909-2915. 10.1093/brain/awu255
  • Herring, A., Donath, A., Steiner, K.M., Widera, M.P., Hamzehian, S., Kanakis, D., Kölble, K., ElAli, A., Hermann, D.M., Paulus, W. & Keyvani, K. Reelin depletion is an early phenomenon of Alzheimer’s pathology. J Alzheimers Dis 30, 963-979. 10.3233/JAD-2012-112069
  • Herring, A., Donath, A., Yarmolenko, M., Uslar, E., Conzen, C., Kanakis, D., Bosma, C., Worm, K., Paulus, W. & Keyvani, K. Exercise during pregnancy mitigates Alzheimer-like pathology in mouse offspring. FASEB J 26, 117-128. 10.1096/fj.11-193193

  • Dodel, R., Balakrishnan, K., Keyvani, K., Deuster, O., Neff, F., Andrei-Selmer, L.C., Röskam, S., Stuer, C., Al-Abed, Y., Noelker, C., Balzer-Geldsetzer, M., Oertel, W., Du, Y. & Bacher, M. Naturally occurring autoantibodies against beta-amyloid: investigating their role in transgenic animal and in vitro models of Alzheimer’s disease. J Neurosci 31, 5847-5854. 10.1523/JNEUROSCI.4401-10.2011
  • Herring, A., Lewejohann, L., Panzer, A.L., Donath, A., Kroll, O., Sachser, N., Paulus, W. & Keyvani, K. Preventive and therapeutic types of environmental enrichment counteract beta amyloid pathology by different molecular mechanisms. Neurobiol Dis 42, 530-538. 10.1016/j.nbd.2011.03.007
  • Herring, A., Blome, M., Ambree, O., Sachser, N., Paulus, W. & Keyvani, K. Reduction of cerebral oxidative stress following environmental enrichment in mice with Alzheimer-like pathology. Brain Pathol 20, 166-175. 10.1111/j.1750-3639.2008.00257.x
  • Ambree, O., Richter, H., Sachser, N., Lewejohann, L., Dere, E., de Souza Silva, M.A., Herring, A., Keyvani, K., Paulus, W. & Schabitz, W.R. Levodopa ameliorates learning and memory deficits in a murine model of Alzheimer’s disease. Neurobiol Aging 30, 1192-1204. 10.1016/j.neurobiolaging.2007.11.010
  • Herring, A., Ambree, O., Tomm, M., Habermann, H., Sachser, N., Paulus, W. & Keyvani, K. Environmental enrichment enhances cellular plasticity in transgenic mice with Alzheimer-like pathology. Exp Neurol 216, 184-192. 10.1016/j.expneurol.2008.11.027

  • Bacher, M., Dodel, R., Aljabari, B., Keyvani, K., Marambaud, P., Kayed, R., Glabe, C., Görtz, N., Hoppmann, A., Sachser, N., Klotsche, J., Schnell, S., Lewejohann, L. & Al-Abed, Y. CNI-1493 inhibits Abeta production, plaque formation, and cognitive deterioration in an animal model of Alzheimer’s disease. J Exp Med 205, 1593-1599. 10.1084/jem.20060467
  • Görtz, N., Lewejohann, L., Tomm, M., Ambree, O., Keyvani, K., Paulus, W. & Sachser, N. Effects of environmental enrichment on exploration, anxiety, and memory in female TgCRND8 Alzheimer mice. Behav Brain Res 191, 43-48. 10.1016/j.bbr.2008.03.006
  • Herring, A., Yasin, H., Ambree, O., Sachser, N., Paulus, W. & Keyvani, K. Environmental enrichment counteracts Alzheimer’s neurovascular dysfunction in TgCRND8 mice. Brain Pathol 18, 32-39. 10.1111/j.1750-3639.2007.00094.x
  • Ambree, O., Leimer, U., Herring, A., Görtz, N., Sachser, N., Heneka, M.T., Paulus, W. & Keyvani, K. Reduction of amyloid angiopathy and Abeta plaque burden after enriched housing in TgCRND8 mice: involvement of multiple pathways. Am J Pathol 169, 544-552. 10.2353/ajpath.2006.051107
  • Ambree, O., Touma, C., Görtz, N., Keyvani, K., Paulus, W., Palme, R. & Sachser, N. Activity changes and marked stereotypic behavior precede Abeta pathology in TgCRND8 Alzheimer mice. Neurobiol Aging 27, 955-964. 10.1016/j.neurobiolaging.2005.05.009

Schwarze-Eicker, K., Keyvani, K., Görtz, N., Westaway, D., Sachser, N. & Paulus, W. Prion protein (PrPc) promotes beta-amyloid plaque formation. Neurobiol Aging 26, 1177-1182. 10.1016/j.neurobiolaging.2004.10.004

Touma, C., Ambree, O., Görtz, N., Keyvani, K., Lewejohann, L., Palme, R., Paulus, W., Schwarze-Eicker, K. & Sachser, N. Age- and sex-dependent development of adrenocortical hyperactivity in a transgenic mouse model of Alzheimer’s disease. Neurobiol Aging 25, 893-904. 10.1016/j.neurobiolaging.2003.09.004

Multiple Sclerosis

(contact: Junker)

Background

Multiple sclerosis (MS) is the most frequent demyelinating disease of the central nervous system (CNS). It affects approximately 2.8 million people worldwide with major individual and socio-economic consequences. MS lesions are characterized by chronic inflammation, demyelination, attenuated remyelination and axonal loss. The latter is considered the main reason for permanent clinical disability of patients. A deeper understanding of the above named pathophysiological processes is necessary for developing more efficient therapeutic approaches.

Research Project

The Role of deregulated microRNAs in grey and white matter lesions

MicroRNAs are endogenous 19–25 nucleotide RNAs that have emerged as a novel class of important gene-regulatory molecules involved in many critical developmental and cellular functions. The aim of this projects is to better understand the role of deregulated microRNAs in grey and white matter lesions as well as their impact on dysregulatedcytokine milieu within the demyelination areas.

Publications

  • Thümmler K., Wrzos C., Franz J., McElroy D., Cole JJ., Hayden L., Arseni D., Schwarz F., Junker A., Edgar JM., Kügler S., Neef A., Wolf F., Stadelmann C., Linington C. Fibroblast growth factor 9 (FGF9)-mediated neurodegeneration: Implications for progressive multiple sclerosis? Neuropathol Appl Neurobiol 49, e12935. 10.1111/nan.12935.
  • Callegari I., Oechtering J., Schneider M., Perriot S., Mathias A., Voortman., M.M., Cagol A., Lanner U., Diebold M., Holdermann S., Kreiner V., Becher B., Granziera C., Junker A., Du Pasquier R., Khalil M., Kuhle J., Kappos L., Sanderson NSR., Derfuss T. Cell-binding IgM in CSF is distinctive of multiple sclerosis and targets the iron transporter SCARA5. Brain, in press.
  • Escolà JK., Deuschl C., Junker A., Dusse F., Pul R., Kleinschnitz C., Köhrmann M., Frank B. MOG antibody-associated encephalomyelitis mimicking bacterial meningomyelitis following ChAdOx1 nCoV-19 vaccination: a case report. Ther Adv Neurol Disord 19. 10.1177/17562864211070684.
  • Teuber-Hanselmann S., Worm K., Macha N., Junker A. MGMT-Methylation in Non-Neoplastic Diseases of the Central Nervous System. Int J Mol Sci 8, 3845. 10.3390/ijms22083845.
  • Jäckle, K., Zeis, T., Schaeren-Wiemers, N., Junker, A., van der Meer, F., Kramann, N., Stadelmann, C. & Brück, W. Molecular signature of slowly expanding lesions in progressive multiple sclerosis. Brain 143, 2073-2088.
  • Junker, A., Wozniak, J., Voigt, D., Scheidt, U., Antel, J., Wegner, C., Brück, W. & Stadelmann, C. Extensive subpial cortical demyelination is specific to multiple sclerosis. Brain Pathol 30, 641-652.
  • Fritsche, L., Teuber-Hanselmann, S., Soub, D., Harnisch, K., Mairinger, F. & Junker, A. MicroRNA profiles of MS gray matter lesions identify modulators of the synaptic protein synaptotagmin-7. Brain Pathol 30, 524-540.
  • Teuber-Hanselmann, S., Meinl, E. & Junker, A. MicroRNAs in gray and white matter multiple sclerosis lesions: impact on pathophysiology. J Pathol 250, 496-509.
  • Harnisch, K., Teuber-Hanselmann, S., Macha, N., Mairinger, F., Fritsche, L., Soub, D., Meinl, E. & Junker, A. Myelination in Multiple Sclerosis Lesions Is Associated with Regulation of Bone Morphogenetic Protein 4 and Its Antagonist Noggin. Int J Mol Sci 20, 154.
  • Schultz, V., van der Meer, F., Wrzos, C., Scheidt, U., Bahn, E., Stadelmann, C., Brück, W. & Junker, A. Acutely damaged axons are remyelinated in multiple sclerosis and experimental models of demyelination. Glia 65, 1350-1360.
  • Voigt, D., Scheidt, U., Derfuss, T., Brück, W. & Junker, A. Expression of the Antioxidative Enzyme Peroxiredoxin 2 in Multiple Sclerosis Lesions in Relation to Inflammation. Int J Mol Sci 18, 760.
  • Gerdes, L.A., Held, K., Beltrán, E., Berking, C., Prinz, J.C., Junker, A., Tietze, J.K., Ertl-Wagner, B., Straube, A., Kümpfel, T., Dornmair, K. & Hohlfeld, R. CTLA4 as Immunological Checkpoint in the Development of Multiple Sclerosis. Ann Neurol 80, 294-300.
  • Abdelhak, A., Junker, A., Brettschneider, J., Kassubek, J., Ludolph, A.C., Otto, M. & Tumani, H. Brain-Specific Cytoskeletal Damage Markers in Cerebrospinal Fluid: Is There a Common Pattern between Amyotrophic Lateral Sclerosis and Primary Progressive Multiple Sclerosis? Int J Mol Sci 16, 17565-88.
  • Mohan, H., Friese, A., Albrecht, S., Krumbholz, M., Elliott, C.L., Arthur, A., Menon, R., Farina, C., Junker, A., Stadelmann, C., Barnett, S.C., Huitinga, I., Wekerle, H., Hohlfeld, R., Lassmann, H., Kuhlmann, T., Linington, C. & Meinl, E. Transcript profiling of different types of multiple sclerosis lesions yields FGF1 as a promoter of remyelination. Acta Neuropathol Commun 2, 168.
  • Junker, A. MicroRNA regulation in multiple sclerosis. MicroRNAs in Medicine. Edited by Charles H. Lawrie. John Wiley & Sons, 1. Edition.
  • Junker, A. & Brück, W. Autoinflammatory grey matter lesions in humans: cortical encephalitis, clinical disorders, experimental models. Curr Opin Neurol 25, 349-57.
  • Lescher, J., Paap, F., Schultz, V., Redenbach, L., Scheidt, U., Rosewich, H., Nessler, S., Fuchs, E., Gärtner, J., Brück, W. & Junker, A. MicroRNA regulation in experimental autoimmune encephalomyelitis in mice and marmosets resembles regulation in human multiple sclerosis lesions. J Neuroimmunol 246, 27-33.
  • Eisele, S., Krumbholz, M., Fischer, M.T., Mohan, H., Junker, A., Arzberger, T., Hohlfeld, R., Bradl, M., Lassmann, H. & Meinl, E. Prospects of Transcript Profiling for mRNAs and MicroRNAs Using Formalin-Fixed and Paraffin-Embedded Dissected Autoptic Multiple Sclerosis Lesions. Brain Pathol 22, 607-18.
  • Junker, A. Pathophysiology of translational regulation by microRNAs in multiple sclerosis. FEBS Lett 585, 3738-46.
  • Junker, A., Meinl, E. & Hohlfeld, R. Emerging role of miRNAs in multiple sclerosis. Nat Rev Neurol 7, 56-59.
  • Mohan, H., Krumbholz, M., Sharma, R., Eisele, S., Junker, A., Sixt, M., Newcombe, J., Wekerle, H., Hohlfeld, R., Lassmann, H. & Meinl, E. Extracellular matrix in multiple sclerosis lesions: Fibrillar collagens, biglycan and decorin are upregulated and associated with infiltrating immune cells. Brain Pathol 20, 966-75.
  • Junker, A., Krumbholz, M., Eisele, S., Mohan, H., Augstein, F., Bittner, R., Lassmann, H., Wekerle, H., Hohlfeld, R. & Meinl, E. MicroRNA profiling of multiple sclerosis lesions identifies modulators of the regulatory protein CD47. Brain 132, 3342-52.
  • Meinl, E., Krumbholz, M., Derfuss, T., Junker, A. & Hohlfeld, R. Compartmentalization of inflammation in the CNS: a major mechanism driving progressive multiple sclerosis. J Neurol Sci 274, 42-44.
  • Junker, A., Ivanidze, J., Malotka, J., Eiglmeier, I., Lassmann, H., Wekerle, H., Meinl, E., Hohlfeld, R. & Dornmair, K. Multiple sclerosis: T-cell receptor expression in distinct brain regions. Brain 130, 2789-99.
  • Krumbholz, M., Theil, D., Steinmeyer, F., Cepok, S., Hemmer, B., Hofbauer, M., Farina, C., Derfuss, T., Junker, A., Arzberger, T., Sinicina, I., Hartle, C., Newcombe, J., Hohlfeld, R. & Meinl, E. CCL19 is constitutively expressed in the CNS, up-regulated in neuroinflammation, active and also inactive multiple sclerosis lesions. J Neuroimmunol 190, 72-79.
  • Brettschneider, J., Petzold, A., Junker, A. & Tumani, H. Axonal damage markers in the cerebrospinal fluid of patients with clinically isolated syndrome improve predicting conversion to definite multiple sclerosis. Multiple sclerosis 12, 143-148.