Katharina Schindowski

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• Prof PhD
• Professor (Full) at University of Applied Sciences Biberach

The transport of small molecules, peptides and proteins via the olfactory epithelium and along olfactory and trigeminal nerve pathways from the nasal cavity to the brain is very well known and clinically established for central nervous system (CNS) active drugs like oxytocin, sumatriptan or insulin. Insulin is a clinically well-established biopharm...

Alzheimer's disease (AD) is a devastating neurodegenerative form of dementia with increasing incidence rates in most countries. AD is characterized by amyloid plaques and neurofibrillary tangles in the brains of AD individuals accompanied by global neuronal loss. The peptide amyloid-β (Aβ) aggregates to amyloid plaques in AD brains. As a result, ma...

Alzheimer's disease (AD) is the most common dementia in the industrialized world, with prevalence rates well over 30% in the over 80-years-old population. The dementia causes enormous costs to the social healthcare systems, as well as personal tragedies for the patients, families and caregivers. AD is strongly associated with Amyloid-beta (Abeta) p...

Neurotrophic factors (NTF) are small, versatile proteins that maintain survival and function to specific neuronal populations. In general, the axonal transport of NTF is important as not all of them are synthesized at the site of its action. Nerve growth factor (NGF), for instance, is produced in the neocortex and the hippocampus and then retrograd...

Tau transgenic mice are valuable models to investigate the role of tau protein in Alzheimer's disease and other tauopathies. However, motor dysfunction and dystonic posture interfering with behavioral testing are the most common undesirable effects of tau transgenic mice. Therefore, we have generated a novel mouse model (THY-Tau22) that expresses h...

Ischemic stroke affects millions of people annually with limited treatment options targeting excitotoxicity, a major cause of cognitive impairment. The PSD-95 inhibitor NA-1 has demonstrated neuroprotective potential, but its efficacy via intravenous administration is hindered by broad systemic distribution, reduced brain exposure, and interaction...

Purpose For optimization of respiratory drug delivery, the selection of suitable in vitro cell models plays an important role in predicting the efficacy and safety of (bio)pharmaceutics and pharmaceutical formulations. Therefore, an in-depth comparison of different primary and permanent in vitro cellular airway models was performed with a focus on...

A region-specific catheter-based intranasal administration method was successfully developed, established, and validated as reported previously. By using this method, drugs can be applicated specifically to the olfactory region. Thereby, intranasally administered drugs could be delivered via neuronal connections to the central nervous system. Here,...

Alzheimer’s disease (AD), most tauopathies, and other neurodegenerative diseases are highly associated to impaired neurotrophin regulation and imbalanced neurotrophin transport and distribution. Neurotrophins are crucial for the survival and maintenance of distinct neuronal population therefore their supply is essential for a healthy brain. Tau pho...

Monoclonal therapeutic antibodies have revolutionized the treatment of cancer and other diseases. Fc engineering aims to enhance the effector functions or half-life of therapeutic antibodies by modifying their Fc regions. Recent advances in the Fc engineering of modern therapeutic antibodies can be considered the next generation of antibody therapy...

Systemic administration of Nogo-A-neutralizing antibody ameliorates experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. However, the blood-brain barrier (BBB) is a major obstacle limiting the passage of systemically applied antibody to the CNS. To bypass the BBB, in the present study we tested the intranasal rout...

During the filling process of a biopharmaceutical drug product (DP), a liquid DP film might creep up the inner vial wall which is barely discernible, appears as milky-white haze after lyophilisation and is known as fogging. Creeping and fogging are mainly dependent on the primary packaging material surface and its hydration, vial preparation proces...

To rationally design intranasal drug delivery systems, i.e., for the assessment of the administered formulation properties, ex vivo porcine nasal mucosa (PNM) explants are one modern but complex standard. Therefore, the development of artificial mucosa substrates as straight-forward PNM analogs is important. The mucosa analog (MA; 5 wt% mucin and 1...

We have recently developed a region-specific catheter-based intranasal application method in mice by using CT scan-based 3D cast models of the murine nose (DOI: 10.2376/0005-9366-17,102). This technique is able to specifically deliver drugs to the olfactory region or to the respiratory region only. Thereby, intranasally administered drugs could be...

IgG antibodies are some of the most important biopharmaceutical molecules with a high market volume. In spite of the fact that clinical therapies with antibodies are broadly utilized in oncology, immunology and hematology, their delivery strategies and biodistribution need improvement, their limitations being due to their size and poor ability to p...

Citation: Maigler, F.; Ladel, S.; Flamm, J.; Gänger, S.; Kurpiers, B.; Kiderlen, S.; Völk, R.; Hamp, C.; Hartung, S.; Spiegel, S.; et al. Selective CNS Targeting and Distribution with a Refined Region-Specific Intranasal Delivery Technique via the Olfactory Mucosa. Pharmaceutics 2021, 13, 1904. Abstract: Intranasal drug delivery is a promising appr...

Intranasal delivery has gained prominence since 1990, when the olfactory mucosa was recognized as the window to the brain and the central nervous system (CNS); this has enabled the direct site specific targeting of neurological diseases for the first time. Intranasal delivery is a promising route because general limitations, such as the blood-brain...

Although we have recently reported the involvement of neonatal Fc receptor (FcRn) in intranasal transport, the transport mechanisms are far from being elucidated. Ex vivo porcine olfactory tissue, primary cells from porcine olfactory epithelium (OEPC) and the human cell line RPMI 2650 were used to evaluate the permeation of porcine and human IgG an...

Antibodies or immunoglobulins are of vital importance for the neutralization of foreign particles like pathogens in the body. As therapeutics, they provide a high potential for many diseases due to their high specificity. For their generation, the establishment of a library (immunized or synthetic) and a selection process for specific binders (disp...

Background: The epithelial layer of the nasal mucosa is the first barrier for drug permeation during intranasal drug delivery. With increasing interest for intranasal pathways, adequate in vitro models are required. Here, porcine olfactory (OEPC) and respiratory (REPC) primary cells were characterised against the nasal tumour cell line RPMI 2650....

Phage display is a powerful technique for drug discovery in biomedical research in particular for antibody libraries. But, several technical challenges are associated with the selection process. For instance, during the panning step, the successful elution of the phages bound to the antigen is critical in order to avoid losing the most promising bi...

The blood-brain barrier and the blood-cerebrospinal fluid barrier are major obstacles in central nervous system (CNS) drug delivery, since they block most molecules from entering the brain. Alternative drug delivery routes like intraparenchymal or intrathecal are invasive methods with a remaining risk of infections. In contrast, nose-to-brain deliv...

Background: The use of therapeutic antibodies for the treatment of neurological diseases is of increasing interest. Nose-to-brain drug delivery is one strategy to bypass the blood brain barrier. The neonatal Fc receptor (FcRn) plays an important role in transepithelial transcytosis of immunoglobulin G (IgG). Recently, the presence of the FcRn was...

The aim of the „3D for 3R“ project was to generate anatomical 3D models of the murine nasal cavity with rapid prototyping to establish a refined region-specific intranasal drug delivery technique targeting either the respiratory or the olfactory epithelium in mice. The anatomical structure of the murine nasal cavity was resolved by x-ray computer t...

Aerosolized administration of biopharmaceuticals to the airways is a promising route for nasal and pulmonary drug delivery, but - in contrast to small molecules - little is known about the effects of aerosolization on safety and efficacy of biopharmaceuticals. Proteins are sensitive against aerosolization-associated shear stress. Tailored formulati...

Alzheimer’s disease (AD), most tauopathies, and other neurodegenerative diseases are highly associated with impaired neurotrophin regulation and imbalanced neutrophin distribution. Tau phosphorylation occurs at different sites of the tau protein and some phospho-epitopes are associated with normal ageing (like tau phosphorylated at Ser202/Thr205 de...

Purpose: Aerosol particle deposition in the human nasal cavity is of high interest in particular for intranasal central nervous system (CNS) drug delivery via the olfactory cleft. The objective of this study was the development and comparison of a numerical and experimental model to investigate various parameters for olfactory particle deposition...

This data article focuses on the production of monoclonal antibodies (mAb) and their fragments Fab and F(ab’)2. Here, we present the data of an optimization protocol to improve the product yield of a hybridoma cell process using a Design of Experiment (DoE) strategy. Furthermore, the data of the evaluated conditions were used to test feeding strate...

Amyloid-beta (Aβ) in Alzheimer's disease (AD) appeared to be a promising target for disease-modifying therapeutic strategies like passive immunotherapy with anti-Aβ monoclonal antibodies (mAbs). Biochemical markers in cerebrospinal fluid (CSF) include alterations of Aβ that allow the diagnosis of AD. Biomarker strategies, such as the levels of Aβ i...

Alzheimer’s disease (AD) is the most common dementia in the industrialized world with prevalence rates far over 30% in the over 80 years old population. The dementia causes enormous cost to the social health care systems besides the personal tragedies for the patients, families and caregivers. One of the pathological protein aggregations that occur...

Background Neurotrophic factors (NTF) play an important role to maintain survival of cholinergic neurons. An imbalance of NTF in Alzheimer's disease (AD) brains is as well known as cholinergic degeneration in the basal forebrain. NGF is synthesized in hippocampal neurons and retrogradly transported to basal forebrain cholinergic neurons (BFCN) whe...

Alzheimer's disease (AD) is a neurodegenerative disorder histologically defined by the cerebral accumulation of amyloid deposits and neurofibrillary tangles composed of hyperphosphorylated tau proteins. Loss of basal forebrain cholinergic neurons is another hallmark of the disease thought to contribute to the cognitive dysfunctions. To this date, t...

GDF-15 is a novel distant member of the TGF-β superfamily and is widely distributed in the brain and peripheral nervous system. We have previously reported that GDF-15 is a potent neurotrophic factor for lesioned dopaminergic neurons in the substantia nigra, and that GDF-15-deficient mice show progressive postnatal losses of motor and sensory neuro...

The invention relates to biparatopic A-beta binding polypeptides and, more specifically, to biparatopic A-beta binding polypeptides comprising at least two immunoglobulin single variable domains binding to different epitopes of A-beta. The invention also relates to specific sequences of such polypeptides, methods of their production, and methods of...

Alzheimer's disease is a neurodegenerative disorder characterized by amyloid deposits and neurofibrillary tangles. Cholinergic dysfunction is also a main pathological feature of the disease. Nevertheless, the links between cholinergic dysfunction and neuropathological hallmarks of Alzheimer's are still unknown. In the present study, we aimed to fur...

Background: In Alzheimer disease (AD), neurofibrillary degeneration (NFD) follows a hierarchical sequential pathway starting in the transentorhinal cortex, then entorhinal cortex and hippocampus and then spreading to temporal areas and other polymodal association areas and finally invading the entire cerebral cortex. This selective neuronal vulnera...

The aim of the present study was to investigate the relation between neurogenesis, cell cycle reactivation and neuronal death during tau pathology in a novel tau transgenic mouse line THY-Tau22 with two frontotemporal dementia with parkinsonism linked to chromosome-17 mutations in a human tau isoform. This mouse displays all Alzheimer disease featu...

The neurotrophin brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) and their cognate receptors, trkB and trkC, have a variety of physiological brain functions, ranging from cell survival to mechanisms involved in learning and memory and long-term potentiation (LTP). LTP can be induced in the cortex and hippocampus, as well as withi...

Neurodegenerative diseases characterized by brain and spinal cord involvement often show widespread accumulations of tau aggregates. We have generated a transgenic mouse line (Tg30tau) expressing in the forebrain and the spinal cord a human tau protein bearing two pathogenic mutations (P301S and G272V). These mice developed age-dependent brain and...

Alzheimer's disease (AD) is the most common progressive neurodegenerative disease. Today, AD affects millions of people worldwide and the number of AD cases will increase with increased life expectancy. The AD brain is marked by severe neurodegeneration like the loss of synapses and neurons, atrophy and depletion of neurotransmitter systems in the...

Neuroinflammation is observed in neurodegenerative diseases like Alzheimer's disease (AD). However, a little is known about the mechanisms of neural-immune interactions. The involvement of peripheral T-cell function in AD is still far from clear, though it plays an important role in immunotherapy. The aim of this study was to determine peripheral T...

Immunotherapy appears to be a potent treatment against Alzheimer's disease (AD), but the mechanisms underlying neural-immune interaction are still not known. Here, we determined cell death and distribution of lymphocyte subsets of peripheral blood mononuclear cells (PBMC) in AD and aging, e.g. T (CD4+ CD3+, CD8+ CD3+), B (CD19+) and NK (CD16++CD56+...

Background: Tau transgenic mice are valuable models to investigate the role of tau protein in Alzheimer’s disease (AD) and other tauopathies. However, motor dysfunction and dystonic posture interfering with behavioral testing are the most common late-life undesirable effects of tau transgenic mice such as any motor impairment severely impairs behav...

Background: Animal models of neurofibrillary degeneration are necessary to investigate the cellular mechanisms leading to different types of neuronal pathology in tauopathies with various clinical phenotypes. Objectives: We have generated a transgenic mouse line (Tau30) expressing in the telencephalon and the spinal cord a human tau protein (1N4R)...

Background: In Alzheimer’s disease (AD) and other tauopathies, some neurons escape to apoptosis and << agonize >> in a process leading to the abnormal phosphorylation of tau proteins and their aggregation. Numerous studies have also reported a reactivation of the cell cycle in parallel to this aggregation process. This cell cycle reactivation is re...

Reactive oxygen species (ROS) have been implicated in neurodegeneration and seem to be involved in the physiology and pathophysiology of several diseases, including normal aging and Alzheimer's disease (AD). Enhanced ROS production in aging or AD is not restricted to the brain, but can also been seen in several peripheral tissues. The objective of...

In large models of neuronal cell death, there is a tight correlation between Cdk5 deregulation and cell-cycle dysfunction. However, pathways that link Cdk5 to the cell cycle during neuronal death are still unclear. We have investigated the molecular events that precede p25/Cdk5-triggered neuronal death using a neuronal cell line that allows inducib...

FGF-2, a potent multifunctional and neurotrophic growth factor, is widely expressed in the brain and upregulated in cerebral ischemia. Previous studies have shown that intraventricularly or systemically administered FGF-2 reduces the size of cerebral infarcts. Whether endogenous FGF-2 is beneficial for the outcome of cerebral ischemia has not been...

The identification of specific genetic (presenilin-1 [PS1] and amyloid precursor protein [APP] mutations) and environmental factors responsible for Alzheimer’s disease (AD) has revealed evidence for a shared pathway of neuronal death. Moreover, AD-specific cell defects may be observed in many other nonneuronal cells (e.g., lymphocytes). Thus, lymph...

As major sources of reactive oxygen species (ROS), mitochondrial structures are exposed to high concentrations of ROS and may therefore be particularly susceptible to oxidative damage. Mitochondrial damage could play a pivotal role in the cell death decision. A decrease in mitochondrial energy charge and redox state, loss of transmembrane potential...

As major sources of reactive oxygen species (ROS), mitochondrial structures are exposed to high concentrations of ROS and may therefore be particularly susceptible to oxidative damage. Mitochondrial damage could play a pivotal role in the cell death decision. A decrease in mitochondrial energy charge and redox state, loss Of transmembrane potential...

The relevance of physiological immune aging is of great interest with respect to determining disorders with pathologic immune function in aging individuals. In recent years, the relevance of changes in peripheral lymphocytes in age-associated neurologic diseases has become more evident. Due to the lack of immunological studies, covering more than o...

Titel auf der Beil. Frankfurt (Main), Univ., Diss., 2001. Optische Speicherplatte.

Many cases of early-onset inherited Alzheimer's disease (AD) are caused by mutations in the presenilin-1 (PS1) gene. Expression of PS1 mutations in cell culture systems and in primary neurons from transgenic mice increases their vulnerability to cell death. Interestingly, enhanced vulnerability to cell death has also been demonstrated for periphera...

Enhanced apoptosis and elevated levels of reactive oxygen species (ROS) play a major role in aging. In addition, several neurodegenerative diseases are associated with increased oxidative stress and apoptosis in neuronal tissue. Antioxidative treatment has neuro-protective effects. The aim of the present study was to evaluate changes of susceptibil...

Alzheimer's disease-related mutations in the presenilin-1 gene (PS1) are leading to an elevated production of neurotoxic β-amyloid 1–42 and may additionally enhance oxidative stress. Here, we provide in vivo evidence indicating that brains of transgenic mice expressing different human Alzheimer-linked PS1 mutations exhibit a reduced activity of two...

Apoptosis seems to be involved in immunosenescence associated with aging. Moreover, in lymphocytes (PBL) of patients with Alzheimer's disease, an increased susceptibility to the apoptotic pathway has been described possibly due to impaired protection of oxidative stress. Accordingly, it seemed to be of particular interest to investigate the contrib...

We have used the tetracycline (tet)-regulated system as described previously to evaluate the applicability of controlled gene expression in cancer gene therapy. As a model gene, we used the human interleukin-2 (IL-2) gene, which has been placed under the transcriptional control of the tetO/promoter. Human melanoma cells were transduced by two modif...

Frankfurt (Main), Univ., Diss., 2001 (Nicht für den Austausch).