20 results on '"Freude, Kristine"'
Search Results
2. Animal and Cellular Models of Alzheimer's Disease.
- Author
-
Baglietto-Vargas, David, Freude, Kristine K., and Garcia-Leon, Juan Antonio
- Subjects
BLOOD-brain barrier ,ALZHEIMER'S disease ,ANIMAL models in research - Abstract
This document is an editorial from the journal Biomedicines that focuses on animal and cellular models of Alzheimer's disease (AD). The editorial highlights the importance of these models in understanding the pathogenic mechanisms of AD and developing clinical applications and therapies. The document discusses key pathological processes in AD, including vascular damage, myelinization, sex differences, and metabolic alterations. It also presents several studies that investigate the role of brain vasculature, astrocytes, microglia, sex differences, and lipid composition in AD. The editorial concludes that these studies contribute to a better understanding of AD pathology and may guide the development of effective therapies. [Extracted from the article]
- Published
- 2024
- Full Text
- View/download PDF
3. Increased glucose metabolism and impaired glutamate transport in human astrocytes are potential early triggers of abnormal extracellular glutamate accumulation in hiPSC-derived models of Alzheimer's disease.
- Author
-
Salcedo, Claudia, Garcia, Victoria Pozo, García-Adán, Bernat, Ameen, Aishat O., Gegelashvili, Georgi, Waagepetersen, Helle S., Freude, Kristine K., and Aldana, Blanca I.
- Subjects
ALZHEIMER'S disease ,GLUTAMINE ,GLYCOLYSIS ,GLUCOSE metabolism ,INDUCED pluripotent stem cells ,ASTROCYTES ,GLUTAMIC acid - Abstract
Glutamate recycling between neurons and astrocytes is essential to maintain neurotransmitter homeostasis. Disturbances in glutamate homeostasis, resulting in excitotoxicity and neuronal death, have been described as a potential mechanism in Alzheimer's disease (AD) pathophysiology. However, glutamate neurotransmitter metabolism in different human brain cells, particularly astrocytes, has been poorly investigated at the early stages of AD. We sought to investigate glucose and glutamate metabolism in AD by employing human induced pluripotent stem cell (hiPSC)-derived astrocytes and neurons carrying mutations in the amyloid precursor protein (APP) or presenilin-1 (PSEN-1) gene as found in familial types of AD (fAD). Methods such as livecell bioenergetics and metabolic mapping using [
13 C]-enriched substrates were used to examine metabolism in the early stages of AD. Our results revealed greater glycolysis and glucose oxidative metabolism in astrocytes and neurons with APP or PSEN-1 mutations, accompanied by an elevated glutamate synthesis compared to control WT cells. Astrocytes with APP or PSEN-1 mutations exhibited reduced expression of the excitatory amino acid transporter 2 (EAAT2), and glutamine uptake increased in mutated neurons, with enhanced glutamate release specifically in neurons with a PSEN-1 mutation. These results demonstrate a hypermetabolic phenotype in astrocytes with fAD mutations possibly linked to toxic glutamate accumulation. Our findings further identify metabolic imbalances that may occur in the early phases of AD pathophysiology. [ABSTRACT FROM AUTHOR]- Published
- 2024
- Full Text
- View/download PDF
4. Astrocytes: The Stars in Neurodegeneration?
- Author
-
Stoklund Dittlau, Katarina and Freude, Kristine
- Subjects
- *
AMYOTROPHIC lateral sclerosis , *ASTROCYTES , *NEURODEGENERATION , *ALZHEIMER'S disease , *PARKINSON'S disease , *NEUROGLIA - Abstract
Today, neurodegenerative disorders like Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) affect millions of people worldwide, and as the average human lifespan increases, similarly grows the number of patients. For many decades, cognitive and motoric decline has been explained by the very apparent deterioration of neurons in various regions of the brain and spinal cord. However, more recent studies show that disease progression is greatly influenced by the vast population of glial cells. Astrocytes are traditionally considered star-shaped cells on which neurons rely heavily for their optimal homeostasis and survival. Increasing amounts of evidence depict how astrocytes lose their supportive functions while simultaneously gaining toxic properties during neurodegeneration. Many of these changes are similar across various neurodegenerative diseases, and in this review, we highlight these commonalities. We discuss how astrocyte dysfunction drives neuronal demise across a wide range of neurodegenerative diseases, but rather than categorizing based on disease, we aim to provide an overview based on currently known mechanisms. As such, this review delivers a different perspective on the disease causes of neurodegeneration in the hope to encourage further cross-disease studies into shared disease mechanisms, which might ultimately disclose potentially common therapeutic entry points across a wide panel of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
5. Potential Retinal Biomarkers in Alzheimer's Disease.
- Author
-
García-Bermúdez, Mariana Yolotzin, Vohra, Rupali, Freude, Kristine, Wijngaarden, Peter van, Martin, Keith, Thomsen, Maj Schneider, Aldana, Blanca Irene, and Kolko, Miriam
- Subjects
ALZHEIMER'S disease ,RETINA ,BIOMARKERS ,RETINAL diseases - Abstract
Alzheimer's disease (AD) represents a major diagnostic challenge, as early detection is crucial for effective intervention. This review examines the diagnostic challenges facing current AD evaluations and explores the emerging field of retinal alterations as early indicators. Recognizing the potential of the retina as a noninvasive window to the brain, we emphasize the importance of identifying retinal biomarkers in the early stages of AD. However, the examination of AD is not without its challenges, as the similarities shared with other retinal diseases introduce complexity in the search for AD-specific markers. In this review, we address the relevance of using the retina for the early diagnosis of AD and the complex challenges associated with the search for AD-specific retinal biomarkers. We provide a comprehensive overview of the current landscape and highlight avenues for progress in AD diagnosis by retinal examination. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
6. Complexity of Sex Differences and Their Impact on Alzheimer's Disease.
- Author
-
Kadlecova, Marion, Freude, Kristine, and Haukedal, Henriette
- Subjects
ALZHEIMER'S disease ,SEX factors in disease ,SEX hormones ,NEURODEGENERATION ,NEUROLOGICAL disorders - Abstract
Sex differences are present in brain morphology, sex hormones, aging processes and immune responses. These differences need to be considered for proper modelling of neurological diseases with clear sex differences. This is the case for Alzheimer's disease (AD), a fatal neurodegenerative disorder with two-thirds of cases diagnosed in women. It is becoming clear that there is a complex interplay between the immune system, sex hormones and AD. Microglia are major players in the neuroinflammatory process occurring in AD and have been shown to be directly affected by sex hormones. However, many unanswered questions remain as the importance of including both sexes in research studies has only recently started receiving attention. In this review, we provide a summary of sex differences and their implications in AD, with a focus on microglia action. Furthermore, we discuss current available study models, including emerging complex microfluidic and 3D cellular models and their usefulness for studying hormonal effects in this disease. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
7. Fats, Friends or Foes: Investigating the Role of Short- and Medium-Chain Fatty Acids in Alzheimer's Disease.
- Author
-
Ameen, Aishat O., Freude, Kristine, and Aldana, Blanca I.
- Subjects
ALZHEIMER'S disease ,FATTY acids ,SHORT-chain fatty acids ,NEURODEGENERATION ,FATS & oils - Abstract
Characterising Alzheimer's disease (AD) as a metabolic disorder of the brain is gaining acceptance based on the pathophysiological commonalities between AD and major metabolic disorders. Therefore, metabolic interventions have been explored as a strategy for brain energetic rescue. Amongst these, medium-chain fatty acid (MCFA) supplementations have been reported to rescue the energetic failure in brain cells as well as the cognitive decline in patients. Short-chain fatty acids (SCFA) have also been implicated in AD pathology. Due to the increasing therapeutic interest in metabolic interventions and brain energetic rescue in neurodegenerative disorders, in this review, we first summarise the role of SCFAs and MCFAs in AD. We provide a comparison of the main findings regarding these lipid species in established AD animal models and recently developed human cell-based models of this devastating disorder. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
8. RhoA Signaling in Neurodegenerative Diseases.
- Author
-
Schmidt, Sissel Ida, Blaabjerg, Morten, Freude, Kristine, and Meyer, Morten
- Subjects
NEURODEGENERATION ,ALZHEIMER'S disease ,HUNTINGTON disease ,AMYOTROPHIC lateral sclerosis ,PARKINSON'S disease ,MOTOR neuron diseases - Abstract
Ras homolog gene family member A (RhoA) is a small GTPase of the Rho family involved in regulating multiple signal transduction pathways that influence a diverse range of cellular functions. RhoA and many of its downstream effector proteins are highly expressed in the nervous system, implying an important role for RhoA signaling in neurons and glial cells. Indeed, emerging evidence points toward a role of aberrant RhoA signaling in neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. In this review, we summarize the current knowledge of RhoA regulation and downstream cellular functions with an emphasis on the role of RhoA signaling in neurodegenerative diseases and the therapeutic potential of RhoA inhibition in neurodegeneration. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
9. APOE4 Affects Basal and NMDAR-Mediated Protein Synthesis in Neurons by Perturbing Calcium Homeostasis.
- Author
-
Ramakrishna, Sarayu, Jhaveri, Vishwaja, Konings, Sabine C., Nawalpuri, Bharti, Chakraborty, Sumita, Holst, Bjørn, Schmid, Benjamin, Gouras, Gunnar K., Freude, Kristine K., and Muddashetty, Ravi S.
- Subjects
APOLIPOPROTEIN E4 ,PROTEIN synthesis ,LABORATORY mice ,CALCIUM ,APOLIPOPROTEIN E ,EMBRYOS - Abstract
Apolipoprotein E (APOE), one of the primary lipoproteins in the brain has three isoforms in humans, APOE2, APOE3, and APOE4. APOE4 is the most well-established risk factor increasing the predisposition for Alzheimer's disease (AD). The presence of the APOE4 allele alone is shown to cause synaptic defects in neurons and recent studies have identified multiple pathways directly influenced by APOE4. However, the mechanisms underlying APOE4-induced synaptic dysfunction remain elusive. Here, we report that the acute exposure of primary cortical neurons or synaptoneurosomes to APOE4 leads to a significant decrease in global protein synthesis. Primary cortical neurons were derived from male and female embryos of Sprague Dawley (SD) rats or C57BL/6J mice. Synaptoneurosomes were prepared from P30 male SD rats. APOE4 treatment also abrogates the NMDA-mediated translation response indicating an alteration of synaptic signaling. Importantly, we demonstrate that both APOE3 and APOE4 generate a distinct translation response which is closely linked to their respective calcium signature. Acute exposure of neurons to APOE3 causes a short burst of calcium through NMDA receptors (NMDARs) leading to an initial decrease in protein synthesis which quickly recovers. Contrarily, APOE4 leads to a sustained increase in calcium levels by activating both NMDARs and L-type voltage-gated calcium channels (LVGCCs), thereby causing sustained translation inhibition through eukaryotic translation elongation factor 2 (eEF2) phosphorylation, which in turn disrupts the NMDAR response. Thus, we show that APOE4 affects basal and activity-mediated protein synthesis responses in neurons by affecting calcium homeostasis. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
10. Downregulation of GABA Transporter 3 (GAT3) is Associated with Deficient Oxidative GABA Metabolism in Human Induced Pluripotent Stem Cell-Derived Astrocytes in Alzheimer's Disease.
- Author
-
Salcedo, Claudia, Wagner, Antonie, Andersen, Jens V., Vinten, Kasper Tore, Waagepetersen, Helle S., Schousboe, Arne, Freude, Kristine K., and Aldana, Blanca I.
- Subjects
GABA transporters ,PLURIPOTENT stem cells ,ALZHEIMER'S disease ,GABA ,INDUCED pluripotent stem cells ,HIGH performance liquid chromatography - Abstract
Alterations in neurotransmitter homeostasis, primarily of glutamate and GABA, is strongly implicated in the pathophysiology of Alzheimer's disease (AD). Homeostasis at the synapse is maintained by neurotransmitter recycling between neurons and astrocytes. Astrocytes support neuronal transmission through glutamine synthesis, which can be derived from oxidative metabolism of GABA. However, the precise implications of astrocytic GABA metabolism in AD remains elusive. The aim of this study was to investigate astrocytic GABA metabolism in AD pathology implementing human induced pluripotent stem cells derived astrocytes. Metabolic mapping of GABA was performed with [U-
13 C]GABA stable isotopic labeling using gas chromatography coupled to mass spectrometry (GC–MS). Neurotransmitter and amino acid content was quantified via high performance liquid chromatography (HPLC) and protein expression was investigated by Western blot assay. Cell lines carrying mutations in either amyloid precursor protein (APP) or presenilin1 (PSEN-1) were used as AD models and were compared to a control cell line of the same genetic background. AD astrocytes displayed a reduced oxidative GABA metabolism mediated by a decreased uptake capacity of GABA, as GABA transporter 3 (GAT3) was downregulated in AD astrocytes compared to the controls. Interestingly, the carbon backbone of GABA in AD astrocytes was utilized to a larger extent to support glutamine synthesis compared to control astrocytes. The results strongly indicate alterations in GABA uptake and metabolism in AD astrocytes linked to reduced GABA transporter expression, hereby contributing further to neurotransmitter disturbances. [ABSTRACT FROM AUTHOR]- Published
- 2021
- Full Text
- View/download PDF
11. Functional Metabolic Mapping Reveals Highly Active Branched-Chain Amino Acid Metabolism in Human Astrocytes, Which Is Impaired in iPSC-Derived Astrocytes in Alzheimer's Disease.
- Author
-
Salcedo, Claudia, Andersen, Jens V., Vinten, Kasper Tore, Pinborg, Lars H., Waagepetersen, Helle S., Freude, Kristine K., and Aldana, Blanca I.
- Subjects
AMINO acid metabolism ,ALZHEIMER'S disease ,ASTROCYTES ,AMYLOID beta-protein precursor ,AMINO acid synthesis - Abstract
The branched-chain amino acids (BCAAs) leucine, isoleucine, and valine are important nitrogen donors for synthesis of glutamate, the main excitatory neurotransmitter in the brain. The glutamate carbon skeleton originates from the tricarboxylic acid (TCA) cycle intermediate α-ketoglutarate, while the amino group is derived from nitrogen donors such as the BCAAs. Disturbances in neurotransmitter homeostasis, mainly of glutamate, are strongly implicated in the pathophysiology of Alzheimer's disease (AD). The divergent BCAA metabolism in different cell types of the human brain is poorly understood, and so is the involvement of astrocytic and neuronal BCAA metabolism in AD. The goal of this study is to provide the first functional characterization of BCAA metabolism in human brain tissue and to investigate BCAA metabolism in AD pathophysiology using astrocytes and neurons derived from human-induced pluripotent stem cells (hiPSCs). Mapping of BCAA metabolism was performed using mass spectrometry and enriched [
15 N] and [13 C] isotopes of leucine, isoleucine, and valine in acutely isolated slices of surgically resected cerebral cortical tissue from human brain and in hiPSC-derived brain cells carrying mutations in either amyloid precursor protein (APP) or presenilin-1 (PSEN-1). We revealed that both human astrocytes of acutely isolated cerebral cortical slices and hiPSC-derived astrocytes were capable of oxidatively metabolizing the carbon skeleton of BCAAs, particularly to support glutamine synthesis. Interestingly, hiPSC-derived astrocytes with APP and PSEN-1 mutations exhibited decreased amino acid synthesis of glutamate, glutamine, and aspartate derived from leucine metabolism. These results clearly demonstrate that there is an active BCAA metabolism in human astrocytes, and that leucine metabolism is selectively impaired in astrocytes derived from the hiPSC models of AD. This impairment in astrocytic BCAA metabolism may contribute to neurotransmitter and energetic imbalances in the AD brain. [ABSTRACT FROM AUTHOR]- Published
- 2021
- Full Text
- View/download PDF
12. Neuronal α‐amylase is important for neuronal activity and glycogenolysis and reduces in presence of amyloid beta pathology.
- Author
-
Byman, Elin, Martinsson, Isak, Haukedal, Henriette, Gouras, Gunnar, Freude, Kristine K., and Wennström, Malin
- Subjects
AMYLASES ,GLYCOGENOLYSIS ,PLURIPOTENT stem cells ,AMYLOID ,PYRAMIDAL neurons ,ALZHEIMER'S patients - Abstract
Recent studies indicate a crucial role for neuronal glycogen storage and degradation in memory formation. We have previously identified alpha‐amylase (α‐amylase), a glycogen degradation enzyme, located within synaptic‐like structures in CA1 pyramidal neurons and shown that individuals with a high copy number variation of α‐amylase perform better on the episodic memory test. We reported that neuronal α‐amylase was absent in patients with Alzheimer's disease (AD) and that this loss corresponded to increased AD pathology. In the current study, we verified these findings in a larger patient cohort and determined a similar reduction in α‐amylase immunoreactivity in the molecular layer of hippocampus in AD patients. Next, we demonstrated reduced α‐amylase concentrations in oligomer amyloid beta 42 (Aβ42) stimulated SH‐SY5Y cells and neurons derived from human‐induced pluripotent stem cells (hiPSC) with PSEN1 mutation. Reduction of α‐amylase production and activity, induced by siRNA and α‐amylase inhibitor Tendamistat, respectively, was further shown to enhance glycogen load in SH‐SY5Y cells. Both oligomer Aβ42 stimulated SH‐SY5Y cells and hiPSC neurons with PSEN1 mutation showed, however, reduced load of glycogen. Finally, we demonstrate the presence of α‐amylase within synapses of isolated primary neurons and show that inhibition of α‐amylase activity with Tendamistat alters neuronal activity measured by calcium imaging. In view of these findings, we hypothesize that α‐amylase has a glycogen degrading function within synapses, potentially important in memory formation. Hence, a loss of α‐amylase, which can be induced by Aβ pathology, may in part underlie the disrupted memory formation seen in AD patients. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
13. Editorial: Metabolic Alterations in Neurodegenerative Disorders.
- Author
-
Freude, Kristine K., Moreno-Gonzalez, Ines, Rodriguez-Ortiz, Carlos J., and Baglietto-Vargas, David
- Subjects
ALZHEIMER'S disease ,METABOLOMICS ,SERIAL publications ,TYPE 2 diabetes ,PARKINSON'S disease ,HUNTINGTON disease ,NEURODEGENERATION - Published
- 2022
- Full Text
- View/download PDF
14. Implications of Glycosylation in Alzheimer's Disease.
- Author
-
Haukedal, Henriette and Freude, Kristine K.
- Subjects
ALZHEIMER'S disease ,INDUCED pluripotent stem cells ,GLYCOSYLATION ,NEUROFIBRILLARY tangles ,AMYLOID plaque ,SENILE dementia - Abstract
Alzheimer's disease (AD) is the most common cause of dementia, affecting millions of people worldwide, and no cure is currently available. The major pathological hallmarks of AD are considered to be amyloid beta plaques and neurofibrillary tangles, generated by respectively APP processing and Tau phosphorylation. Recent evidence imply that glycosylation of these proteins, and a number of other AD-related molecules is altered in AD, suggesting a potential implication of this process in disease pathology. In this review we summarize the understanding of glycans in AD pathogenesis, and discuss how glycobiology can contribute to early diagnosis and treatment of AD, serving as potential biomarkers and therapeutic targets. Furthermore, we look into the potential link between the emerging topic neuroinflammation and glycosylation, combining two interesting, and until recent years, understudied topics in the scope of AD. Lastly, we discuss how new model platforms such as induced pluripotent stem cells can be exploited and contribute to a better understanding of a rather unexplored area in AD. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
15. Cell Type Specific Expression of Toll-Like Receptors in Human Brains and Implications in Alzheimer's Disease.
- Author
-
Frederiksen, Henriette R., Haukedal, Henriette, and Freude, Kristine
- Subjects
ALZHEIMER'S disease treatment ,BRAIN metabolism ,CELL receptors ,ALZHEIMER'S disease ,BRAIN ,CELL physiology ,CYTOKINES ,GENE expression ,MEMBRANE proteins ,TOLL-like receptors - Abstract
Toll-like receptors mediate important cellular immune responses upon activation via various pathogenic stimuli such as bacterial or viral components. The activation and subsequent secretion of cytokines and proinflammatory factors occurs in the whole body including the brain. The subsequent inflammatory response is crucial for the immune system to clear the pathogen(s) from the body via the innate and adaptive immune response. Within the brain, astrocytes, neurons, microglia, and oligodendrocytes all bear unique compositions of Toll-like receptors. Besides pathogens, cellular damage and abnormally folded protein aggregates, such as tau and Amyloid beta peptides, have been shown to activate Toll-like receptors in neurodegenerative diseases such as Alzheimer's disease. This review provides an overview of the different cell type-specific Toll-like receptors of the human brain, their activation mode, and subsequent cellular response, as well as their activation in Alzheimer's disease. Finally, we critically evaluate the therapeutic potential of targeting Toll-like receptors for treatment of Alzheimer's disease as well as discussing the limitation of mouse models in understanding Toll-like receptor function in general and in Alzheimer's disease. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
16. Neurons derived from sporadic Alzheimer's disease iPSCs reveal elevated TAU hyperphosphorylation, increased amyloid levels, and GSK3B activation.
- Author
-
Ochalek, Anna, Mihalik, Balázs, Avci, Hasan X., Chandrasekaran, Abinaya, Téglási, Annamária, Bock, István, Giudice, Maria Lo, Táncos, Zsuzsanna, Molnár, Kinga, László, Lajos, Nielsen, Jørgen E., Holst, Bjørn, Freude, Kristine, Hyttel, Poul, Kobolák, Julianna, and Dinnyés, András
- Subjects
ALZHEIMER'S disease ,FAMILIAL diseases ,INDUCED pluripotent stem cells ,AMYLOID beta-protein ,TAU proteins ,PHOSPHORYLATION - Abstract
Background: Alzheimer's disease (AD) is the most common type of dementia, affecting one in eight adults over 65 years of age. The majority of AD cases are sporadic, with unknown etiology, and only 5% of all patients with AD present the familial monogenic form of the disease. In the present study, our aim was to establish an in vitro cell model based on patient-specific human neurons to study the pathomechanism of sporadic AD. Methods: We compared neurons derived from induced pluripotent stem cell (iPSC) lines of patients with early-onset familial Alzheimer's disease (fAD), all caused by mutations in the PSEN1 gene; patients with late-onset sporadic Alzheimer's disease (sAD); and three control individuals without dementia. The iPSC lines were differentiated toward mature cortical neurons, and AD pathological hallmarks were analyzed by RT-qPCR, enzyme-linked immunosorbent assay, and Western blotting methods. Results: Neurons from patients with fAD and patients with sAD showed increased phosphorylation of TAU protein at all investigated phosphorylation sites. Relative to the control neurons, neurons derived from patients with fAD and patients with sAD exhibited higher levels of extracellular amyloid-ß
1-40 (Aß1-40 ) and amyloid-ß1-42 (Aß1-42 ). However, significantly increased Aß1-42 /Aß1-40 ratios, which is one of the pathological markers of fAD, were observed only in samples of patients with fAD. Additionally, we detected increased levels of active glycogen synthase kinase 3 ß, a physiological kinase of TAU, in neurons derived from AD iPSCs, as well as significant upregulation of amyloid precursor protein (APP) synthesis and APP carboxy-terminal fragment cleavage. Moreover, elevated sensitivity to oxidative stress, as induced by amyloid oligomers or peroxide, was detected in both fAD- and sAD-derived neurons. Conclusions: On the basis of the experiments we performed, we can conclude there is no evident difference except secreted Aß1-40 levels in phenotype between fAD and sAD samples. To our knowledge, this is the first study in which the hyperphosphorylation of TAU protein has been compared in fAD and sAD iPSC-derived neurons. Our findings demonstrate that iPSC technology is suitable to model both fAD and sAD and may provide a platform for developing new treatment strategies for these conditions. [ABSTRACT FROM AUTHOR]- Published
- 2017
- Full Text
- View/download PDF
17. Metabolic effects of the retina in a murine model of AD (TgSwDI).
- Author
-
García‐Bermúdez, Mariana Yolotzin, Vohra, Rupali, Freude, Kristine, Thomsen, Maj Schneider, Aldana, Blanca Irene, and Kolko, Miriam
- Subjects
TISSUE viability ,TISSUE metabolism ,BIOLUMINESCENCE assay ,RETINA ,ALZHEIMER'S disease - Abstract
* Shared co‐author. Purpose: Previous cerebral studies of Alzheimer's disease (AD) have provided evidence for a neuronal metabolic dysfunction, which precede the cognitive decline. Since the retina is one of the most energy demanding tissues in the body and considered an extension of the brain due to its origin from the neural tissue, we speculate whether dysfunctional energy metabolism is present in AD models. Thus, the aim of the study is to evaluate energy metabolism and tissue survival in retinal explants in a murine model of AD (TgSwDI) during aging. Methods: The 8‐, 12‐, and 24‐month‐old TgSwDI mouse model was compared with age‐matched wild‐type (WT) mice. Tissue survival was assessed by lactate dehydrogenase (LDH) viability assays of retinal explants at 2, 4 and 24 hours of incubation with culture media. Total ATP levels were quantified by bioluminescence assays to assess energy metabolism in TgSwDI mice. Results: Retinal explant survival was reduced in the TgSwDI model compared to the age‐matched WT model with LDH assay at 8 months. The 8‐month‐old AD TgSwDI mice showed a tendency to decrease in total ATP levels after 2 hours of retinal explant incubation (p = 0.07). Conclusions: Retinal tissue survival is impaired in the TgSwDI model during various ages, and tendencies of decreased retinal ATP levels were established at 8 months, implying disrupted retinal energy metabolism similar to changes observed in the AD brain. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
18. Modeling neurodegenerative diseases with patient-derived induced pluripotent cells: Possibilities and challenges.
- Author
-
Poon, Anna, Zhang, Yu, Chandrasekaran, Abinaya, Phanthong, Phetcharat, Schmid, Benjamin, Nielsen, Troels T., and Freude, Kristine K.
- Subjects
- *
TREATMENT of neurodegeneration , *PLURIPOTENT stem cells , *DRUG development , *GENOME editing , *DISEASE prevalence - Abstract
The rising prevalence of progressive neurodegenerative diseases coupled with increasing longevity poses an economic burden at individual and societal levels. There is currently no effective cure for the majority of neurodegenerative diseases and disease-affected tissues from patients have been difficult to obtain for research and drug discovery in pre-clinical settings. While the use of animal models has contributed invaluable mechanistic insights and potential therapeutic targets, the translational value of animal models could be further enhanced when combined with in vitro models derived from patient-specific induced pluripotent stem cells (iPSCs) and isogenic controls generated using CRISPR-Cas9 mediated genome editing. The iPSCs are self-renewable and capable of being differentiated into the cell types affected by the diseases. These in vitro models based on patient-derived iPSCs provide the opportunity to model disease development, uncover novel mechanisms and test potential therapeutics. Here we review findings from iPSC-based modeling of selected neurodegenerative diseases, including Alzheimer’s disease, frontotemporal dementia and spinocerebellar ataxia. Furthermore, we discuss the possibilities of generating three-dimensional (3D) models using the iPSCs-derived cells and compare their advantages and disadvantages to conventional two-dimensional (2D) models. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
19. The transcriptomic landscape of neurons carrying PSEN1 mutations reveals changes in extracellular matrix components and non-coding gene expression.
- Author
-
Corsi, Giulia I., Gadekar, Veerendra P., Haukedal, Henriette, Doncheva, Nadezhda T., Anthon, Christian, Ambardar, Sheetal, Palakodeti, Dasaradhi, Hyttel, Poul, Freude, Kristine, Seemann, Stefan E., and Gorodkin, Jan
- Subjects
- *
EXTRACELLULAR matrix , *GENE expression , *CHRONIC traumatic encephalopathy , *CIRCULAR RNA , *CALBINDIN , *GENETIC variation , *NEURONS , *GENE ontology - Abstract
Alzheimer's disease (AD) is a progressive and irreversible brain disorder, which can occur either sporadically, due to a complex combination of environmental, genetic, and epigenetic factors, or because of rare genetic variants in specific genes (familial AD, or fAD). A key hallmark of AD is the accumulation of amyloid beta (Aβ) and Tau hyperphosphorylated tangles in the brain, but the underlying pathomechanisms and interdependencies remain poorly understood. Here, we identify and characterise gene expression changes related to two fAD mutations (A79V and L150P) in the Presenilin-1 (PSEN1) gene. We do this by comparing the transcriptomes of glutamatergic forebrain neurons derived from fAD-mutant human induced pluripotent stem cells (hiPSCs) and their individual isogenic controls generated via precision CRISPR/Cas9 genome editing. Our analysis of Poly(A) RNA-seq data detects 1111 differentially expressed coding and non-coding genes significantly altered in fAD. Functional characterisation and pathway analysis of these genes reveal profound expression changes in constituents of the extracellular matrix, important to maintain the morphology, structural integrity, and plasticity of neurons, and in genes involved in calcium homeostasis and mitochondrial oxidative stress. Furthermore, by analysing total RNA-seq data we reveal that 30 out of 31 differentially expressed circular RNA genes are significantly upregulated in the fAD lines, and that these may contribute to the observed protein-coding gene expression changes. The results presented in this study contribute to a better understanding of the cellular mechanisms impacted in AD neurons, ultimately leading to neuronal damage and death. • Extracellular matrix components are altered in fAD neurons compared to controls • Merging GENCODE and FANTOM-CAT annotations improves lncRNA identification in RNA-seq • CircRNAs are predominantly upregulated in fAD neurons compared to controls • Competing endogenous RNAs may contribute to gene expression modulation in fAD [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
20. Swedish Alzheimer Mutation Induces Mitochondrial Dysfunction Mediated by HSP60 Mislocalization of Amyloid Precursor Protein (APP) and Beta-Amyloid.
- Author
-
Walls, Ken Carlson, Coskun, Pinar, Gallegos-Perez, Jose Luis, Zadourian, Nineli, Freude, Kristine, Rasool, Suhail, Blurton-Jones, Mathew, Green, Kim Nicholas, and LaFerla, Frank Michael
- Subjects
- *
ALZHEIMER'S disease , *MITOCHONDRIAL pathology , *PROTEOMICS , *HEAT shock proteins , *AMYLOID beta-protein precursor , *AMYLOID beta-protein - Abstract
Alzheimer disease (AD) is a complex disorder that involves numerous cellular and subcellular alterations including impairments in mitochondrial homeostasis. To better understand the role of mitochondrial dysfunction in the pathogenesis of AD, we analyzed brains from clinically well-characterized human subjects and from the 3xTg-AD mouse model of AD. We find Aβ and critical components of the γ-secretase complex, presenilin-1, -2, and nicastrin, accumulate in the mitochondria. We used a proteomics approach to identify binding partners and show that heat shock protein 60 (HSP60), a molecular chaperone localized to mitochondria and the plasma membrane, specifically associates with APP. We next generated stable neural cell lines expressing human wild-type or Swedish APP, and provide corroborating in vitro evidence that HSP60 mediates translocation of APP to the mitochondria. Viral-mediated shRNA knockdown of HSP60 attenuates APP and Aβ mislocalization to the mitochondria. Our findings identify a novel interaction between APP and HSP60, which accounts for its translocation to the mitochondria. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.