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Projects

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

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. 

Principal investigator: dr.sc. Silva Katušić Hećimović

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

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.

Principal investigator: dr.sc. Silva Katušić Hećimović

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

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.

Principal investigator: dr.sc. Silva Katušić Hećimović

Tff3 protein at intersection of metabolism and neurodegeneration

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.

Principal investigator: dr.sc. Mirela Baus Lončar

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

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

FP7-PEOPLE-2013-IEF

Principal investigator: dr.sc. Silva Katušić Hećimović

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

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. 

Principal investigator: dr.sc. Silva Katušić Hećimović

Lysosomal dysfunction as a common mechanism of neurodegenerative diseases

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.

Principal investigator: dr.sc. Silva Katušić Hećimović

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

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. 

Principal investigator: dr.sc. Silva Katušić Hećimović

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

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.

Principal investigator: dr.sc. Silva Katušić Hećimović

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

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.

Principal investigator: dr.sc. Silva Katušić Hećimović

Laboratory for Neurodegenerative Disease Research

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