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Neuroageing and Neurodegeneration

The molecular mechanisms underlying physiological ageing of the human brain and its link to ageing-associated neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disesese (PD), are still poorly understood. Moreover, the role of exposure to exogenous noxae in brain ageing and/or neurodegenerative processes is unclear. Several environmental agents, such as heavy metals, pesticides, solvent exposure and nanomaterials have been implicated with inconsistent results. Thus, the need for greatly intensified research in this area is obvious.

Alzheimer's disease

A common theme in neurodegenerative disease is the occurrence of aberrant protein conformations and the subsequent formation of insoluble protein deposits. Conclusive evidence supports the amyloid hypothesis stating that accumulation of amyloidoigenic Aβ42 peptides in the brain plays a causal role in Alzheimer’s disease (AD).

Despite considerable progress in the understanding of the molecular pathogenesis of AD and Parkinson’s disease (PD), the second most common neurodegenerative disorder, intense efforts to develop effective therapies have so far not yielded a breakthrough, and only symptomatic treatments are available today. Importantly, neuropathology and imaging studies indicate that brain accumulation of Aβ peptides begins in cognitively normal individuals 10-20 years before the clinical onset of AD.

Today, neuropsychological testing provides approximately 85% accuracy in the diagnosis of AD. However, this diagnosis is based on substantial cognitive impairments, with patients at this stage already having suffered extensive neuronal damage. These findings indicate that the future of AD therapeutics is not treatment in advanced stages but prevention. However, early intervention in cognitively normal individuals requires approaches that strongly prioritise safety and a reliable method to identify individuals at risk for AD. Thus, the development of methods for early diagnosis and for therapy monitoring is one of the most pressing areas of dementia research. These issues are one centre of attention in NND.

PIs

Researchers at the IUF Leibniz Research Institute for Environmental Medicine (Jean Krutmann, Ellen Fritsche, Anna von Mikecz) study the influence of specific noxae, in particular organic pollutants and nanoparticles, on neurodegenerative processes and protein aggregation in vitro and in animal models of AD (Chen et al., J Cell Biol 2008; von Mikecz, Trends Cell Biol 2009; Arnhold and von Mikecz, Integr. Biology 2011). Additional mechanistic studies investigate pathways contributing to brain ageing in mice and man, including thyroid hormone signaling and the impact of oxidative stress. The role of fine particulate matter-induced mild cognitive impairment in humans is addressed in epidemiological studies (Ranft, Environ Res 2009).

Carsten Korth's laboratory conceptualizes neuronal aging as a dysbalance of protein homeostasis (proteostasis). In that sense, subtle changes in the amounts of insoluble proteins are expected and have been demonstrated to appear during non-disease-related aging correlating to aging associated cognitive decline (Ottis et al. PLoS One. 2013). Similarly, the well-known strictly age-associated accumulation of autofluorescent material, lipofuscin, is conceived as the expression of dysbalanced protein metabolism. The Korth laboratory recently analyzed the identity of protein components of lipofuscin (Ottis et al. Proteomics. 2012). We are currently working on determining the lipofuscin proteome by laser microdissection of human post mortem tissue (Tschirner, Korth et al., manuscript in preparation).
Carsten Korth is currently coordinating a BMBF-funded National network for investigating autofluorecent material and degeneration in CNS (http://www.gesundheitsforschung-bmbf.de/de/5765.php).

The laboratory of Carsten Korth is investigating the pathology of misfolded proteins like those of Abeta or the prion protein. Carsten Korth has made leading contributions to the development of conformer-specific antibodies, including the first antibody against the disease-associated conformation of the prion protein (Korth, Nature 1997).

Publication of a transgenic mouse model expressing exclusively Abeta dimers ("tgDimer mouse"; Müller-Schiffmann et al. 2015 Brain) but no other Abeta multimers, including insoluble Abeta plaques, but nevertheless displaying learning and memory deficits, has further established the importance of Abeta oligomers in Alzheimer's disease pathogenesis (see also video on youtube). This tgDimer mouse is an animal model for early AD since in addition to the cognitive deficits it displays also depressive-like behaviors (Abdel-Hafiz, Neurobiol Aging, 2018). See also the accompanying video on the tgDimer mouse.

Earlier work in collaboration with Kurt Gottmann had established that specific mutations leading to the exclusive formation of Abeta dimers in vitro and in vivo are functional and enable investigation of this specific conformational subpopulation of Abeta (Müller-Schiffmann et al. 2011 ACS Chem Neurosci).

Therapy of Alzheimer's disease is a focus of the Korth laboratory. Two directions are pursued: 1. The identification of Abeta assembly machines (Marreiros et al. Virus Res. 2015) where Abeta assembly is conceptualized as similar to viral capsid assembly, and 2. The development of hybrid drugs (Korth et al. Curr Top Med Chem. 2013; Müller-Schiffmann et al. BioDrugs. 2012).

In an interdisciplinary effort involving Kurt Gottmann and Dieter Willbold among others, hybrid compounds were designed and synthesized that disrupt beta-sheets in Abeta multimers and restitute Abeta-induced dysfunctionality (Müller-Schiffmann, Angew Chem Int Ed Engl 2010). Nanoparticle-based hybrid drugs are the latest development (Streich, ACS Nano, 2016).

Neurodegeneration can also occur in early-onset pediatric diseases. There, an imbalance of cellular bioenergetics may impair neuronal homeostasis causing neurodevelopmental failure and premature aging-like neurodegeneration. This is the case for example of familial Huntington’s disease (HD) and pediatric mitochondrial disorders.

The group of Alessandro Prigione investigates these diseases using patient-derived induced pluripotent stem cells (iPSCs) differentiated into 2D neuronal and glial cultures and 3D cerebral organoids (Lorenz et al, Cell Stem Cell 2017; Scior et al, EMBO J 2018; Inak et al, Stem Cells 2017).

Birgit Strodel and her team use computer simulations to unravel how and why Aβ aggregates into toxic oligomers. They were among the first ones to simulate the oligomer formation of Aβ beyond the dimer state and revealed that the shape of the oligomers is decisive for the aggregation pathway (Barz et al., J. Am. Chem. Soc. 2018).

The team also modelled the interactions between Aβ and lipid membranes since the neuronal membrane is not only able to stimulate the formation of Aβ oligomers, it is also a site of AD toxicity, as Aβ has been shown to harm membrane integrity disrupting the Ca2+ balance of neurons. Their simulations revealed that oligomers as small as tetramers in a β-sheet conformation lead to an increased membrane permeability (Poojari et al., BBA-Biomembranes 2013).

Other physiological factors, such as metal ions, inflammation leading to acidosis, and oxidative stress are also putative modulators of AD. Strodel et al. showed that the structural equilibrium of Aβ dimers is shifted towards β-sheet rich and thus aggregation-prone structures as a result of Cu2+ binding, oxidative stress and mild acidic conditions (Liao et al., Israel J. Chem. 2017).

Natascia Ventura has pioneered the concept of mitochondria-double edge sword by showing in the past that different degrees of mitochondrial stress, achieved through genetic or pharmacological suppression of different mitochondria respiratory chain subunit, can lead to opposite outcomes on animal health span. Based on those  key findings her laboratory has since specialized on different aspects of mitochondria-regulated neurodegenerative processes associated with either early-onset genetic disorders (Maglioni and Ventura, 2016) or aging (Schiavi et al., 2020). The lab has a long-term expertise in addressing the role of mitochondria adaptive responses in regulating aging  and associated neurodegenerative disorders (e.g. Alzheimer and Parkinson diseases) primarily using the nematode C. elegans as a powerful genetic tractable model organism for aging studies (Schiavi et al., 2015; Torgovnick et al., 2018; Brinkmann et al., 2020). Dr. Ventura has recently coordinated a European project nationally funded by the BMBF and currently holds two DFG grants, all investigating how different dietary components or contaminants possibly impact on mitochondria to regulate neuronal aging and associated diseases.

Moreover, the lab has recently developed novel C. elegans models to study different Mitochondriopathies with a particular focus on Complex I deficiency (e.g. Leigh Syndrome, Maglioni et al. BioRxiv). The overall goal of the lab is to promote health span through the identification of novel mitochondria-regulated processes exploitable for targeted preventive or therapeutic strategies. A goal which is achieved also thanks to a recently developed platform for in vivo high-content phenotype-based screening (Maglioni et al., 2015) and to newly generated mammalian disease models.

Sascha Weggen has pioneered the concept of γ-secretase modulation in AD therapeutics (Weggen, Nature 2001; Czirr, J Biol Chem 2008; Richter, PNAS 2010). γ-Secretase modulators are small molecules that cause a product shift from Aβ42 towards shorter and less toxic Aβ peptides. Recently, second-generation modulators with improved pharmacological properties have become available, and these are candidate drugs for AD prevention studies. The lab addresses the molecular mechanism of γ-secretase modulators and their efficacy in AD mouse models. This includes the development of novel classes of γ-secretase modulators and of chemical tools to probe the mechanism of intramembrane proteolysis by γ-secretase.

The group of Dieter Willbold is focused on the analysis of protein ligand-interactions by various methods including surface plasmon resonance and NMR spectroscopy. A particular focus lies on proteins relevant for neurodegenerative diseases.

For early diagnostics of AD, the team has developed the ultra-sensitive sFIDA assay (surface-based fluorescence intensity distribution analysis) which quantifies Aβ oligomers in CSF as a disease biomarker. In a first proof of concept study this method was succesfully used to differentiate between healthy controls, MCI- and AD patients. Moreover, the readout correlated with the severity of cognitive decline (Wang-Dietrich et al., J Alzheimers Dis. 2013). Current work focuses on standardization and higher sample throughput (Kühbach et al., Front Neurosci 2016).

The lab also developed an innovative therapeutic approach based on D-enantiomeric peptides selected by mirror image phage display against Aβ. The lead compound has been further developed into a drug candidate which in vitro specifically eliminates Aβ oligomers, the most toxic Aβ aggregate species. In vivo, oral treatment with the drug candidate reduces amyloid plaque load, cerebral inflammation and cognitive impairment in several AD mouse models. (Van Groen et al., ChemMedChem 2008; Van Groen et al., ChemMedChem 2009; Funke et al., ACS Chem Neurosci. 2010; Van Groen et al., Adv Protein Chem Struct Biol. 2012; Van Groen et al., J Alzheimer's Dis. 2013; Brener et al., Sci Rep 2015). After further preclinical testing has shown promising properties for the lead compound and a derivative (Jiang et al., PLoS One 2015; Leithold et al., Pharm Res 2016) the researchers are now aiming to carry out a clinical phase I study with the drug candidate in the next months. Ongoing projects aim to identify D-peptide-based drug candidates for other neurodegenerative diseases.

The collaborative research program of the DFG research training group RTG 1033 (ended 2014), which involved 12 research groups from HHU and the IUF Leibniz Research Institute for Environmental Medicine, was primarily focused on the investigation of molecular mechanisms in brain ageing and their possible links with ageing-associated neurodegenerative processes, including the investigation of strategies for prevention or delay of neurodegeneration during ageing.

Specifically, the roles of (1) oxidative stress and aging-associated gene expression, (2) aging-dependend synaptic transmission and cognitive changes, as well as the (3) detection, cellular degradation and prevention of toxic protein aggregates were addressed in collaborative multidisciplinary doctoral research projects.

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