Laboratory for Neurodegenerative Disease Research

Laboratory for Neurodegenerative Disease Research

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The goal of the Laboratory for Neurodegenerative Disease Research (LAND) is to discover fundamental mechanisms of neurodegenerative diseases and to translate new understandings into prevention, diagnosis and treatments. The Laboratory combines independent and collaborative research on molecular and cellular neuroscience, the use of different in vitro, ex vivo and in vivo models and the biomarker research.  

The Laboratory for Neurodegenerative Disease Research aims towards competitive and internationally recognized research, continuous training of the researchers and intensive national and international collaboration.

The main research areas of the Laboratory are:

  • Molecular mechanism(s) of Alzheimer’s disease, in particular the role of lipids in the disease pathogenesis
  • Molecular mechanism(s) of neurodegeneration in a rare inherited Niemann-Pick type C disease
  • The role of lysosomal dysfunction and altered vesicular trafficking in the pathogenesis of neurodegenerative disorders
  • Lipid biomarkers of neurodegenerative diseases
  • The role of trefoil factor family protein (Tff3) in metabolism and neurodegeneration
LINB 2017

Kate Šešelja

+385 1 457 1284
1841

Kristina Dominko

+385 1 457 1284
1841

Lea Vidatić

+385 1 457 1284
1841 1593

Mirela Baus Lončar
PhD

Senior Research Associate
+385 1 457 1284
1841

Silva Katušić Hećimović
Doc, Ph.D.

Senior Research Associate
+385 1 457 1327
1593 1841

Katusic Hecimovic group

We have been intrigued by the fact that the two different neurodegenerative disorders, a rare childhood lipid and lysosomal storage disease Niemann-Pick type C (NPC) and the most common and complex Alzheimer's disease (AD), share several key features of neurodegeneration and neuroinflammation, including accumulation of the Alzheimer’s amyloid-beta peptides, increased levels of hyperphosphorylated tau, dysfunction of the endolysosomal pathway, apolipoprotein E ε4 allele as a risk factor and strong activation of astrocyte and microglia.

Slide1

However, these two disorders also show clear neuropathological distinctions. In contrast to AD where neurodegeneration primarily occurs in the brain regions of hippocampus and cortex, while cerebellum seems to be protected, in NPC disease Purkinje neurons in the cerebellum are most affected, while hippocampus seems to be spared. Using different mouse models, primary neurons and glia cells, organotypic brain slices as well as cell lines our goal is to elucidate molecular details of similarities and different brain region vulnerabilities between these two neurodegenerative disorders. These studies will increase our understanding of the molecular pathogenesis of these conditions, as well as our chances of finding disease-modifying therapies.

Slide4

Baus Loncar group

Alzheimers  disease (AD) comes in 90% of cases as sporadic one without clear genetic markers. Human and preclinical studies have provided convincing evidence that AD is a degenerative metabolic disease, mediated by impaired insulin responsiveness in the brain, glucose utilization and energy metabolism. The connection between diabetes/obesity and AD, may shed light how sporadic AD develops. Biomarker search in cerebrospinal fluid of  AD  patients  identified  TFF3 protein as a new  possible candidate for this crosstalk. Tff3 protein is present in neurons and liver produced Tff3 can act neuroprotective and concentrate in brain upon injury. Our goal is to elucidate the role of Tff3 protein  in liver/brain axis using Tff3 -/-mouse strain and modeling metabolic relevant conditions. This systemic approach will help us understand common pathways in diabesity and neurodegeneration and possibly reveal novel therapeutic targets.

Slide1
Molecular mechanism(s) of neurodegeneration in  Niemann-Pick type C disease

Molecular mechanism(s) of neurodegeneration in Niemann-Pick type C disease

Glavni istraživač / voditelj: Silva Katušić Hećimović

The goal of this project is to elucidate the molecular mechanism(s) of neurodegeneration in Niemann-Pick type C disease (NPC). We will investigate the role of protease BACE1, the key Alzheimer's disease (AD) enzyme, in the pathogenesis of NPC disease. We hope that our findings will elucidate BACE1 as a novel target for treating/ameliorating NPC disease.

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Tff3 protein at intersection of metabolism and neurodegeneration

Tff3 protein at intersection of metabolism and neurodegeneration

Glavni istraživač / voditelj: Mirela Baus Lončar

In this project  proposal we will investigate impact of Tff3 protein in liver/brain axis using Tff3 -/-mouse strain and modeling Type 1 and Type 2 diabesity conditions. We will correlate  the effect  of Tff3 deficiency on liver as major metabolic organ,  and hippocampus/cortex as affected brain regions is AD, monitoring neurodegenerative hallmarks and endoplasmatic reticulum stress markers. Using novel technology (XFe96 Extracellular Flux Analyzer) we will estimate impact of Tff3 on mitochondrial respiration and glycolysis in living primary hepatocytes. This systemic approach will help us understand common pathways in diabesity and neurodegeneration and possibly reveal novel therapeutic targets.

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Elucidating BACE1 as a potential target for treating Niemann-Pick type C disease

Elucidating BACE1 as a potential target for treating Niemann-Pick type C disease

Glavni istraživač / voditelj: Silva Katušić Hećimović

BACE1 The β-secretase, known as β-site amyloid precursor protein cleavage enzyme 1 (BACE1), plays a central role in Alzheimer’s disease (AD) pathogenesis as it initiates processing of APP and the production of the toxic amyloid-β peptides (Aβ) that accumulate in the brains of AD patients. BACE1 has become a prime therapeutic target for lowering Aβ, and clinical development of BACE1 inhibitors is being intensely pursued as avenue for treatment of AD. Interestingly, a rare inherited - yet untreatable - lysosomal storage disorder Niemann-Pick type C (NPC) and AD have several key features in common. We have recently shown that APP cleavage by BACE1 is significantly enhanced in NPC1-model cells vs. wt cells..In light with the recently discovered similarities between AD and NPC, the goal of this project is to elucidate the role of BACE1 in the pathogenesis of NPC and whether BACE1 may represent a novel target for treating/ameliorating NPC disease.

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Elucidating BACE1-substrate processing and distribution in a transgenic mouse model of Alzheimer’s disease

Elucidating BACE1-substrate processing and distribution in a transgenic mouse model of Alzheimer’s disease

Glavni istraživač / voditelj: Silva Katušić Hećimović

Recent failures of clinical trials against Alzheimer’s disease (AD) with γ-secretase inhibitors have shifted the focus to BACE1 as a key AD drug target. However, the complex phenotypes of BACE1-null mice and the numerous recently identified BACE1 substrates suggest that the inhibition of BACE1 may cause unacceptable side-effects. This emphasizes the need to investigate more thoroughly the mechanisms of action of this enzyme and the functions of its substrates. The goal of this project is to characterize the processing and distribution of the two top BACE1 substrates, seizure protein 6 (Sez6) and seizure 6-like protein (Sez6L) in a transgenic (tg) mouse model of Alzheimer’s disease. In line with the recently identified accumulation of BACE1 in human and tg-mouse AD brains we propose that accumulation of BACE1 within presynaptic terminals and enhanced cleavage of its substrates at or near the synapse, in addition to APP, may add to synaptic (dys)function, learning and memory deficits, neurodegeneration and the pathogenesis of Alzheimer’s disease. 

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BrainProtect - Presenilin 2 - a protector against Alzheimer's disease

BrainProtect - Presenilin 2 - a protector against Alzheimer's disease

Glavni istraživač / voditelj: Silva Katušić Hećimović

Marie Curie Actions - Intra-European Fellowship for Career Development (IEF)

FP7-PEOPLE-2013-IEF

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The molecular links between cholesterol homeostasis, membrane trafficking and Alzheimer's disease

The molecular links between cholesterol homeostasis, membrane trafficking and Alzheimer's disease

Glavni istraživač / voditelj: Silva Katušić Hećimović

Aberrant proteolytic cleavage of the amyloid precursor protein (APP) leading to increased formation/accumulation of β-amyloid peptide (Aβ) is considered a central event in the pahogenesis of Alzheimer's disease (AD). Although much has been known about the Aβ generation and its clearance, we still do not understand in great detail how Aβ metabolism is altered in the most common late-onset form of AD (LOAD) and what are the molecular trigger(s) that initiate these events. In this project we will test the hypothesis that cholesterol metabolism and membrane trafficking are tightly linked and that their dysregulation leads to Alzheimer's disease. 

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Lysosomal dysfunction as a common mechanism of neurodegenerative diseases

Lysosomal dysfunction as a common mechanism of neurodegenerative diseases

Glavni istraživač / voditelj: Silva Katušić Hećimović

Using a lysosomal disorder NPC as a model, the goal of this project is to investigate a role of lysosomal impairment on accumulation of amyloid-beta peptide (Abeta) and alpha-synuclein (a-syn), the two characteristic features in the pathogenesis of AD and PD.

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Molecular mechanism(s) of cholesterol-effect on APP and BACE1 metabolism  - the two key proteins of Alzheimer's disease

Molecular mechanism(s) of cholesterol-effect on APP and BACE1 metabolism - the two key proteins of Alzheimer's disease

Glavni istraživač / voditelj: Silva Katušić Hećimović

The goal of this project was to further elucidate the mechanism/s of cholesterol-effect on the metabolism of APP and BACE1 – the two key proteins in the pathogenesis of Alzheimer's disease. Using biochemical, molecular biological and cell biological approaches we have tested the hypotheses that alterations in cholesterol metabolism (due to NPC1 dysfunction) contribute to accumulation of Abeta and the pathogenesis of AD by modulating endocytic trafficking of BACE1 and/or by modulating lysosomal/autophagic function. 

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Alzheimer's disease - the role of cholesterol on processing and localization of APP-family members

Alzheimer's disease - the role of cholesterol on processing and localization of APP-family members

Glavni istraživač / voditelj: Silva Katušić Hećimović

This project aims to analyze whether the molecular mechanisms of the cholesterol effect on APP and amyloid-β peptide (Aβ) may involve APP-family members, APLP1 and APLP2.  We will elucidate whether cholesterol affects processing of APLP1 and APLP2, like APP, and whether the cholesterol effect on APP is mediated by APLP1/2-regulated trafficking of APP.

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The mechanism of cholesterol action in the pathogenesis of Alzheimer’s disease

The mechanism of cholesterol action in the pathogenesis of Alzheimer’s disease

Glavni istraživač / voditelj: Silva Katušić Hećimović

Recent studies reveal that cholesterol may play a role in the pathogenesis of Alzheimer’s disease (AD). The goal of this project is to elucidate the mechanism(s) of cholesterol-effect on APP metabolism, formation of amyloid-β peptide (Aβ)  and the genesis of Alzheimer’s disease. We speculate that cholesterol regulation of membrane and protein trafficking along the endocytic pathway leads to amyloidogenic processing of APP and Aβ formation.

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Cermak S, Kosicek M, Mladenovic-Djordjevic A, Smiljanic K, Kanazir S, Hecimovic S. (2016) Loss of Cathepsin B and L Leads to Lysosomal Dysfunction, NPC-Like Cholesterol Sequestration and Accumulation of the Key Alzheimer's Proteins.PLoS One. 11(11):e0167428. doi: 10.1371/journal.pone.0167428.

Drechsler S, Lynch MA, Novella S, González-Navarro H, Hecimovic S, Barini E, Tucci V, Castro RE, Vandenbroucke RE, Osuchowski M, Potter PK. (2016) With mouse age comes wisdom: A review and suggestions of relevant mouse models for age-related conditions. Mechanisms of Ageing and Development. 160:54-68. doi: 10.1016/j.mad.2016.07.005.

Malnar M, Hecimovic S, Mattsson M, Zetterberg H. (2014) Bidirectional links between Alzheimer's disease and Niemann-Pick type C disease. Neurobiology of Disease, Neurobiol Dis 72 Pt A: 37.

Kosicek M, Wunderlich P, Walter J, Hecimovic S. (2014) GGA1 overexpression attenuates amyloidogenic processing of APP inNPC1-null cells.Biochemical and Biophysical Research Communications,450: 160-5.

Kosicek M, Hecimovic S. (2013) Phospholipids and Alzheimer’s disease: alterations, mechanisms and potential biomerkers. International Journal of Molecular Sciences 14: 1310-22.

von Einem B, Weber P, Wagner M, Malnar M, Kosicek M, Hecimovic S, von Arnim C, Schneckenburger H. (2012) Cholesterol dependent energy transfer between fluorescent proteins - insights into protein proximity of APP and BACE1 in different membranes in Niemann-Pick type C disease cells. International Journal of Molecular Sciences. 13: 15801-12.

Mattsson N, Olsson M, Gustavsson MK, Kosicek M, Malnar M, Månsson JE, Blomqvist M, Gobom J, Andreasson U, Brinkmalm G, Vite C, Hecimovic S, Hastings C, Blennow K, Zetterberg H, Portelius E. (2012)  Amyloid-β metabolism in Niemann-Pick C disease models and patients. Metabolic Brain Disease. 27:573-585.

Malnar M, Kosicek M, Lisica A, Posavec M, Krolo A, Njavro J, Omerbasic D, Tahirovic S, Hecimovic S. (2012) Cholesterol-depletion corrects APP and BACE1 misstrafficking in NPC1-deficient cells. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease1822: 1270-83.

Kosicek M, Zetterberg H, Andreasen N, Peter-Katalinic J, Hecimovic S. (2012) Elevated cerebrospinal fluid sphingomyelin levels in prodromal Alzheimer's disease. Neuroscience Letters516: 302-5.

Kosicek M, Malnar M, Goate A, Hecimovic S. (2010) Cholesterol accumulation in Niemann Pick type C (NPC) model cells causes a shift in APP localization to lipid rafts. Biochemical and Biophysical Research Communications 393: 404-9.

Malnar M, Kosicek M, Mitterreiter S, Omerbasic D, Lichtenthaler SF, Goate A, Hecimovic S. (2010) Niemann Pick type C cells show cholesterol dependent decrease of APP expression at the cell surface its increased processing through the β-secretase pathway. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease 1802: 682-91

Kosicek M, Kirsch S, Bene R, Trkanjec Z, Titlic M, Bindila L, Peter-Katalinic J, Hecimovic S. (2010) Nano-HPLC-MS analysis of phospholipids in cerebrospinal fluid of Alzheimer's disease patients-a pilot study. Analytical and Bioanalytical Chemistry 98: 2929-37.

Hecimovic S, Wang J, Martinez M, Goate A (2004) Mutations in APP have independent effects on Aβ and CTFγ generation. Neurobiology of Disease 17: 205-218.

Cam JA, Zerbinatti CV, Knisely JM, Hecimovic S, Yonghe L, Bu G (2004) The LDL receptor-related protein 1B retains APP at the cell surface and reduces amyloid-β peptide production. Journal of Biological Chemistry 279: 29639-46.

Wang J, Brunkan AL, Hecimovic S, Walker E, Goate A (2004) Conserved “PAL” sequence in presenilins is essential for γ-secretase activity, but not required for formation or stabilization of γ-secretase complex. Neurobiology of Disease 15: 654-666.

Schroeter EH, Ilagan MXG, Brunkan AL, Hecimovic S, Li Y-M, Xu M, Lewis HD, Saxena MT, De Strooper B, Coonrod A, Tomita T, Iwatsubo T, Moore CL, Shearman M, Goate A, Wolfe MS, Kopan R (2003) A presenilin dimer at the core of the gamma-secretase enzyme: insights from parallel analysis of Notch 1 and APP proteolysis. Proceedings of the National Academy of Sciences USA 100: 13075-80. 

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