scholarly journals Neuron-glia interaction through Serotonin-BDNF-NGFR axis enables regenerative neurogenesis in Alzheimer’s model of adult zebrafish brain

2019 ◽  
Author(s):  
Prabesh Bhattarai ◽  
Mehmet Ilyas Cosacak ◽  
Violeta Mashkaryan ◽  
Sevgican Yilmaz ◽  
Stanislava Dimitrova Popova ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Experimental Models ◽  
Interleukin 4 ◽  
List Type ◽  
Adult Zebrafish ◽  
Bdnf Expression ◽  
Zebrafish Brain ◽  
Amyloid Toxicity ◽  
The Brain

AbstractIt was recently suggested that supplying the brain with new neurons could counteract Alzheimer’s disease. This provocative idea requires further testing in experimental models where the molecular basis of disease-induced neuronal regeneration could be investigated. We previously found that zebrafish stimulates neural stem cell (NSC) plasticity and neurogenesis in Alzheimer’s disease and could help to understand the mechanisms to be harnessed for develop new neurons in diseased mammalian brains. Here, by performing single-cell transcriptomics, we found that Amyloid toxicity-induced Interleukin-4 induces NSC proliferation and neurogenesis by suppressing the tryptophan metabolism and reducing the production of Serotonin. NSC proliferation was suppressed by Serotonin via downregulation of BDNF-expression in Serotonin-responsive periventricular neurons. BDNF enhances NSC plasticity and neurogenesis via NGFRA/NFkB signaling in zebrafish but not in rodents. Collectively, our results suggest a complex neuron-glia interaction that regulates regenerative neurogenesis after Alzheimer’s disease conditions in zebrafish.Key findings-Amyloid-induced Interleukin-4 suppresses Serotonin (5-HT) production in adult zebrafish brain-5-HT affects htr1-expresing neurons and suppresses bdnf expression-BDNF enhances plasticity in neural stem cells via NGFRA/NFkB signaling-BDNF/NGFRA signaling is a neuro-regenerative mechanism in zebrafish but not in mammals.

scholarly journals Single cell analyses of the effects of Amyloid-beta42 and Interleukin-4 on neural stem/progenitor cell plasticity in adult zebrafish brain

2018 ◽  
Author(s):  
Mehmet Ilyas Cosacak ◽  
Prabesh Bhattarai ◽  
Yixin Zhang ◽  
Caghan Kizil
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Stem Cells ◽  
Neural Stem Cells ◽  
Single Cell ◽  
Drug Targets ◽  
Disease Model ◽  
Interleukin 4 ◽  
Adult Zebrafish ◽  
Zebrafish Brain

AbstractNeural stem cells (NSCs) constitute the reservoir for new cells and might be harnessed for stem cell-based regenerative therapies. Zebrafish has remarkable ability to regenerate its brain by inducing NSC plasticity upon Alzheimer’s pathology. We recently identified that NSCs enhance their proliferation and neurogenic outcome in an Amyloid-beta42-based (Aβ42) experimental Alzheimer’s disease model in zebrafish brain and Interleukin-4 (IL4) is a critical molecule for inducing NSC proliferation in AD conditions. However, the mechanisms by which Aβ42 and IL4 affect NSCs remained unknown. Using single cell transcriptomics, we determined distinct subtypes of NSCs and neurons in adult zebrafish brain, identified differentially expressed genes after Aβ42 and IL4 treatments, analyzed the gene ontology and pathways that are affected by Aβ42 and IL4, and investigated how cell-cell communication is altered through secreted molecules and their receptors. Our results constitute the most extensive resource in the Alzheimer’s disease model of adult zebrafish brain, are likely to provide unique insights into how Aβ42/IL4 affects NSC plasticity and yield in novel drug targets for mobilizing neural stem cells for endogenous neuro-regeneration.

scholarly journals KYNA/Ahr Signaling Suppresses Neural Stem Cell Plasticity and Neurogenesis in Adult Zebrafish Model of Alzheimer’s Disease

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2748
Author(s):  
Tohid Siddiqui ◽  
Prabesh Bhattarai ◽  
Stanislava Popova ◽  
Mehmet Ilyas Cosacak ◽  
Sanjeev Sariya ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Stem Cell ◽  
Neural Stem Cell ◽  
Late Onset ◽  
Association Studies ◽  
Neural Regeneration ◽  
Adult Zebrafish ◽  
Amyloid Toxicity ◽  
Model Of Alzheimer’S Disease

Neurogenesis decreases in Alzheimer’s disease (AD) patients, suggesting that restoring the normal neurogenic response could be a disease modifying intervention. To study the mechanisms of pathology-induced neuro-regeneration in vertebrate brains, zebrafish is an excellent model due to its extensive neural regeneration capacity. Here, we report that Kynurenic acid (KYNA), a metabolite of the amino acid tryptophan, negatively regulates neural stem cell (NSC) plasticity in adult zebrafish brain through its receptor, aryl hydrocarbon receptor 2 (Ahr2). The production of KYNA is suppressed after amyloid-toxicity through reduction of the levels of Kynurenine amino transferase 2 (KAT2), the key enzyme producing KYNA. NSC proliferation is enhanced by an antagonist for Ahr2 and is reduced with Ahr2 agonists or KYNA. A subset of Ahr2-expressing zebrafish NSCs do not express other regulatory receptors such as il4r or ngfra, indicating that ahr2-positive NSCs constitute a new subset of neural progenitors that are responsive to amyloid-toxicity. By performing transcriptome-wide association studies (TWAS) in three late onset Alzheimer disease (LOAD) brain autopsy cohorts, we also found that several genes that are components of KYNA metabolism or AHR signaling are differentially expressed in LOAD, suggesting a strong link between KYNA/Ahr2 signaling axis to neurogenesis in LOAD.

scholarly journals Folic Acid Deficiency and Homocysteine Impair DNA Repair in Hippocampal Neurons and Sensitize Them to Amyloid Toxicity in Experimental Models of Alzheimer's Disease

2002 ◽  
Vol 22 (5) ◽  
pp. 1752-1762 ◽  
Author(s):  
Inna I. Kruman ◽  
T. S. Kumaravel ◽  
Althaf Lohani ◽  
Ward A. Pedersen ◽  
Roy G. Cutler ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dna Repair ◽  
Folic Acid ◽  
Hippocampal Neurons ◽  
Experimental Models ◽  
Folic Acid Deficiency ◽  
Amyloid Toxicity ◽  
Acid Deficiency

scholarly journals Amyloid accumulation drives proteome-wide alterations in mouse models of Alzheimer’s disease like pathology

2017 ◽  
Author(s):  
Jeffrey N. Savas ◽  
Yi-Zhi Wang ◽  
Laura A. DeNardo ◽  
Salvador Martinez-Bartolome ◽  
Daniel B. McClatchy ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Expression ◽  
Mouse Models ◽  
Ampa Receptor ◽  
Proteomic Analysis ◽  
Protein Networks ◽  
Causative Role ◽  
List Type ◽  
The Brain

SummaryAmyloid beta (Aβ) peptides impair multiple cellular pathways in the brain and play a causative role in Alzheimer’s disease (AD) pathology, but how the brain proteome is remodeled during this process is unknown. To identify new protein networks associated with AD-like pathology, we performed global quantitative proteomic analysis in three mouse models at pre- and post-symptomatic ages. Our analysis revealed a robust and consistent increase in Apolipoprotein E (ApoE) levels in nearly all transgenic brain regions with increased Aβ levels. Taken together with prior findings on ApoE driving Aβ accumulation, this analysis points to a pathological dysregulation of the ApoE-Aβ axis. We also found dysregulation of protein networks involved in excitatory synaptic transmission consistent with AD pathophysiology. Targeted analysis of the AMPA receptor complex revealed a specific loss of TARPγ-2, a key AMPA receptor trafficking protein. Expression of TARPγ-2 in vivo in hAPP transgenic mice led to a restoration of AMPA currents. This database of proteome alterations represents a unique resource for the identification of protein alterations responsible for AD.HighlightsProteomic analysis of mouse brains with AD-like pathology reveals stark remodelingProteomic evidence points to a dysregulation of ApoE levels associated with Aβ clearance rather than productionCo-expression analysis found distinctly impaired synapse and mitochondria modulesIn-depth analyses of AMPAR complex points to loss of TARPγ-2, which may compromise synapses in ADeTOC BlurbProteome-wide profiling of brain tissue from three mouse models of AD-like pathology reveals Aβ, brain region, and age dependent alterations of protein levels. This resource provides a new global protein expression atlas for the Alzheimer’s disease research community.

scholarly journals A Study of the SORL1 Gene in the Pathogenesis of Late-onset Alzheimer’s Disease by Affecting the Expression of BDNF

2021 ◽  
Author(s):  
Mingri Zhao ◽  
Jiangfeng Liu ◽  
Jingli He ◽  
Xun Chen ◽  
Yanjin Feng ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Cell Model ◽  
Amyloid Β ◽  
Cognitive Disorders ◽  
Amyloid Β Protein ◽  
Bdnf Expression ◽  
The Brain

Abstract BackgroundAlzheimer’s disease is a neurodegenerative disease characterized by progressive memory impairment and other cognitive disorders. It is divided into Familial Alzheimer's disease (FAD) and Sporadic Alzheimer's disease (SAD). SAD is also called delayed Late-onset Alzheimer's disease (LOAD). Sortilin Related Receptor 1 (SORL1) is a high-risk pathogenic gene of LOAD, which can participate in the occurrence and development of AD by affecting the transport and metabolism of intracellular β-amyloid precursor protein (APP). The expression of SORL1 is significantly downregulated in patients with LOAD.ResultsIn the SORL1 knockout (SORL1 KO) mouse model constructed by CRISPR/cas9, we found that the expression of Brain Derived Neurotrophic Factor (BDNF) in the brain of SORL1 KO mice was significantly down-regulated and Amyloid β-protein (Aβ) deposition was found in the brain ofSORL1 KO mice. Through the SORL1 knockdown N2a cell model constructed by shRNA, we also found that when the SORL1 expression was knocked down, the BDNF expression was also downregulated and the cell viability decreased. The results of immunohistochemistry and in vitro cell model experiments suggest that the downregulation of BDNF caused by SORL1 knockdown may be mainly achieved by affecting the expression and distribution of N-Methyl-D-aspartate (NMDAR).ConclusionsSORL1 knockout changes the expression and distribution of NMDAR in cells, downregulates the expression of BDNF, and thus affects the learning and memory of mice.

Evidence for a neuroprotective role for corticotropin-releasing hormone against amyloid toxicity in experimental models of Alzheimer's disease

2000 ◽  
Vol 21 ◽  
pp. 86
Author(s):  
W.A. Pedersen ◽  
D. McCullers ◽  
C. Culmsee ◽  
M. Killen ◽  
J.P. Herman ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Experimental Models ◽  
Corticotropin Releasing Hormone ◽  
Releasing Hormone ◽  
Amyloid Toxicity

CT features of atrophy of the brain temporal lobes characteristic for Alzheimer’s disease with different stages of dementia

2011 ◽  
Vol 26 (S2) ◽  
pp. 941-941
Author(s):  
I.V. Maksimovich
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Control Group ◽  
Study Group ◽  
List Type ◽  
Type Number ◽  
Severe Dementia ◽  
Temporal Lobes ◽  
Clinical Stages ◽  
The Brain

BackgroundWhile diagnosing Alzheimer’s disease, there appear certain difficulties in the correlation of cerebral atrophy and the patient's clinical status.Methods93 patients were examined.Study group - 42 patients aged 34-79 with preclinical and clinical stages of Alzheimer’s disease:(1)- patients with high risk of acquiring the disease (those suffering from impaired memory, without any manifestations of dementia, whose 2 or more immediate relatives suffered from Alzheimer’s disease) 6 patients(2)- patients with mild dementia 14(3)- patients with moderate dementia 15(4)- patients with severe dementia 7Control group - 51 patients aged 28–78 with various kinds of brain lesions accompanied by dementia but not suffering from Alzheimer’s disease:-chronic cerebrovascular insufficiency 21 patients-severe vascular dementia 6-atherosclerotic parkinsonism 14-Binswanger’s disease 6-Parkinson’s disease 4ResultsIn Study group 1, 4 (66.6%) patients showed decrease of 4–8% in the size of the brain temporal lobes.In Study group 2, 14 (100%) patients showed decrease of 9–18%.In Study group 3, 15 (100%) patients showed decrease of 19–32%.In Study group 4, 7 (100%) patients showed decrease of 33–62%.Control group patients had no similar changes in the temporal lobes.ConclusionsStructural and morphological changes of the brain characteristic for Alzheimer’s disease are atrophy of the temporal lobes and hippocampus which makes 4–8% in pre-clinical stages of the disease, 9–18% in mild, 19–32% in moderate and 33–62% in severe dementia.

scholarly journals Environmental Enrichment Effects on the Brain-Derived Neurotrophic Factor Expression in Healthy Condition, Alzheimer’s Disease, and Other Neurodegenerative Disorders

2021 ◽  
pp. 1-18
Author(s):  
Debora Cutuli ◽  
Eugenia Landolfo ◽  
Laura Petrosini ◽  
Francesca Gelfo
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurotrophic Factor ◽  
Environmental Enrichment ◽  
Brain Plasticity ◽  
Regulation Of Gene Expression ◽  
Experimental Studies ◽  
Brain Derived Neurotrophic Factor ◽  
Bdnf Expression ◽  
The Brain

Brain-derived neurotrophic factor (BDNF), a protein belonging to the neurotrophin family, is known to be heavily involved in synaptic plasticity processes that support brain development, post-lesion regeneration, and cognitive performances, such as learning and memory. Evidence indicates that BDNF expression can be epigenetically regulated by environmental stimuli and thus can mediate the experience-dependent brain plasticity. Environmental enrichment (EE), an experimental paradigm based on the exposure to complex stimulations, constitutes an efficient means to investigate the effects of high-level experience on behavior, cognitive processes, and neurobiological correlates, as the BDNF expression. In fact, BDNF exerts a key role in mediating and promoting EE-induced plastic changes and functional improvements in healthy and pathological conditions. This review is specifically aimed at providing an updated framework of the available evidence on the EE effects on brain and serum BDNF levels, by taking into account both changes in protein expression and regulation of gene expression. A further purpose of the present review is analyzing the potential of BDNF regulation in coping with neurodegenerative processes characterizing Alzheimer’s disease (AD), given BDNF expression alterations are described in AD patients. Moreover, attention is also paid to EE effects on BDNF expression in other neurodegenerative disease. To investigate such a topic, evidence provided by experimental studies is considered. A deeper understanding of environmental ability in modulating BDNF expression in the brain may be fundamental in designing more tuned and effective applications of complex environmental stimulations as managing approaches to AD.

scholarly journals Using Drosophila Models of Amyloid Toxicity to Study Autophagy in the Pathogenesis of Alzheimer’s Disease

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Louise O’Keefe ◽  
Donna Denton
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuronal Function ◽  
Amyloid Toxicity ◽  
Cellular Pathways ◽  
Toxic Peptides ◽  
The Brain ◽  
Prevalent Form ◽  
Drosophila Models

Autophagy is a conserved catabolic pathway that involves the engulfment of cytoplasmic components such as large protein aggregates and organelles that are delivered to the lysosome for degradation. This process is important in maintaining neuronal function and raises the possibility of a role for autophagy in neurodegenerative diseases. Alzheimer’s disease (AD) is the most prevalent form of these diseases and is characterized by the accumulation of amyloid plaques in the brain which arise due to the misfolding and aggregation of toxic peptides, including amyloid beta (Aβ). There is substantial evidence from both AD patients and animal models that autophagy is dysregulated in this disease. However, it remains to be determined whether this is protective or pathogenic as there is evidence that autophagy can act to promote the degradation as well as function in the generation of toxic Aβ peptides. Understanding the molecular details of the extensive crosstalk that occurs between the autophagic and endolysosomal cellular pathways is essential for identifying the molecular details of amyloid toxicity. Drosophila models that express the toxic proteins that aggregate in AD have been generated and have been shown to recapitulate hallmarks of the disease. Here we focus on what is known about the role of autophagy in amyloid toxicity in AD from mammalian models and how Drosophila models can be used to further investigate AD pathogenesis.

Longitudinal Changes in Individual BrainAGE in Healthy Aging, Mild Cognitive Impairment, and Alzheimer’s Disease

GeroPsych ◽  
2012 ◽  
Vol 25 (4) ◽  
pp. 235-245 ◽  
Author(s):  
Katja Franke ◽  
Christian Gaser
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Healthy Aging ◽  
Brain Aging ◽  
Elderly Subjects ◽  
Additional Increase ◽  
Longitudinal Changes ◽  
Novel Method ◽  
The Brain

We recently proposed a novel method that aggregates the multidimensional aging pattern across the brain to a single value. This method proved to provide stable and reliable estimates of brain aging – even across different scanners. While investigating longitudinal changes in BrainAGE in about 400 elderly subjects, we discovered that patients with Alzheimer’s disease and subjects who had converted to AD within 3 years showed accelerated brain atrophy by +6 years at baseline. An additional increase in BrainAGE accumulated to a score of about +9 years during follow-up. Accelerated brain aging was related to prospective cognitive decline and disease severity. In conclusion, the BrainAGE framework indicates discrepancies in brain aging and could thus serve as an indicator for cognitive functioning in the future.

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