scholarly journals 3D Models as an Adjunct for Models in Studying Alzheimer’s Disease

2021 ◽  
Author(s):  
Ahmed Yaqinuddin ◽  
Muhammad Faisal Ikram ◽  
Ayesha Rahman Ambia ◽  
Raghad Alaujan ◽  
Junaid Kashir
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurofibrillary Tangles ◽  
Three Dimensional ◽  
3D Culture ◽  
Amyloid Β ◽  
3D Models ◽  
Culture Models ◽  
Neurological Processes

AbstractAlzheimer’s disease (AD) is one of the most common causes of dementia. Disease progression is marked by cognitive decline and memory impairment due to neurodegenerative processes in the brain stemming from amyloid-β (Aβ) deposition and formation of neurofibrillary tangles. Pathogenesis in AD is dependent on two main neurological processes: formation of intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein and deposition of extracellular senile Aβ peptides. Given the nature of the disease, the pathology and progression of AD in vivo in humans have been difficult to study in vivo. To this degree, models can help to study the disease pathogenesis, biochemistry, immunological functions, genetics, and potential pharmacotherapy. While animal and two-dimensional (2D) cell culture models have facilitated significant progress in studying the disease, more recent application of novel three-dimensional (3D) culture models has exhibited several advantages. Herein, we describe a brief background of AD, and how current animal, 2D, and 3D models facilitate the study of this disease and associated therapeutics.

scholarly journals Impact of four common hydrogels on amyloid-β (Aβ) aggregation and cytotoxicity: Implications for 3D models of Alzheimer’s disease

2019 ◽  
Author(s):  
Laura W. Simpson ◽  
Gregory L. Szeto ◽  
Hacene Boukari ◽  
Theresa A. Good ◽  
Jennie B. Leach
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Type I Collagen ◽  
3D Culture ◽  
Amyloid Β ◽  
Mesh Size ◽  
Correlation Spectroscopy ◽  
Cell Phenotype ◽  
Type I

AbstractThe properties of a hydrogel utilized in 3D culture can influence cell phenotype and morphology, yielding striking similarities to cellular processes that occur in vivo. Indeed, research areas including regenerative medicine, tissue engineering, cancer models, and stem cell cultures have readily utilized 3D biomaterials to investigate cell biological questions. However, cells are only one component of this milieu. Macromolecules play roles as bioactive factors and physical structures. Yet, investigations of macromolecular biophysics largely focus on pure molecules in dilute solution. Biophysical processes such as protein aggregation underlie diseases including Alzheimer’s disease, which is hallmarked by accumulated neurotoxic amyloid-β (Aβ) aggregates. Previously, we demonstrated that Aβ cytotoxicity is attenuated when cells are cultured within type I collagen hydrogels vs. on 2D substrates. Here, we investigated whether this phenomenon is conserved when Aβ is confined within hydrogels of varying physiochemical properties, notably mesh size and bioactivity. We investigated Aβ structure and aggregation kinetics in solution and in hydrogels (collagen, agarose, hyaluronic acid and polyethylene glycol) using fluorescence correlation spectroscopy and thioflavin T assays. Our results reveal that all hydrogels tested were associated with Aβ cytotoxicity attenuation. We suggest that confinement itself imparts a profound effect, possibly by stabilizing Aβ structures and shifting the aggregate equilibrium toward larger species. It is likely that the milieu that exist within cells and tissues also influences protein-protein interactions; thus, we suggest that it is critical to evaluate whether protein structure, function, and stability are altered in 3D systems vs. ideal solutions and 2D culture.

scholarly journals A Super-Resolved View of the Alzheimer’s Disease-Related Amyloidogenic Pathway in Hippocampal Neurons

2021 ◽  
pp. 1-20
Author(s):  
Yang Yu ◽  
Yang Gao ◽  
Bengt Winblad ◽  
Lars Tjernberg ◽  
Sophia Schedin Weiss
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Hippocampal Neurons ◽  
Three Dimensional ◽  
Amyloid Β ◽  
Stimulated Emission ◽  
Amyloid Β Peptide ◽  
Primary Neurons ◽  
Amyloid Β Protein ◽  
Early Endosomes

Background: Processing of the amyloid-β protein precursor (AβPP) is neurophysiologically important due to the resulting fragments that regulate synapse biology, as well as potentially harmful due to generation of the 42 amino acid long amyloid β-peptide (Aβ 42), which is a key player in Alzheimer’s disease. Objective: Our aim was to clarify the subcellular locations of the amyloidogenic AβPP processing in primary neurons, including the intracellular pools of the immediate substrate, AβPP C-terminal fragment (APP-CTF) and the product (Aβ 42). To overcome the difficulties of resolving these compartments due to their small size, we used super-resolution microscopy. Methods: Mouse primary hippocampal neurons were immunolabelled and imaged by stimulated emission depletion (STED) microscopy, including three-dimensional, three-channel imaging and image analyses. Results: The first (β-secretase) and second (γ-secretase) cleavages of AβPP were localized to functionally and distally distinct compartments. The β-secretase cleavage was observed in early endosomes, where we were able to show that the liberated N- and C-terminal fragments were sorted into distinct vesicles budding from the early endosomes in soma. Lack of colocalization of Aβ 42 and APP-CTF in soma suggested that γ-secretase cleavage occurs in neurites. Indeed, APP-CTF was, in line with Aβ 42 in our previous study, enriched in the presynapse but absent from the postsynapse. In contrast, full-length AβPP was not detected in either the pre- or the postsynaptic side of the synapse. Furthermore, we observed that endogenously produced and endocytosed Aβ 42 were localized in different compartments. Conclusion: These findings provide critical super-resolved insight into amyloidogenic AβPP processing in primary neurons.

scholarly journals NLRP3 Inflammasome: A Starring Role in Amyloid-β- and Tau-Driven Pathological Events in Alzheimer’s Disease

2021 ◽  
pp. 1-22
Author(s):  
Mariana Van Zeller ◽  
Diogo M. Dias ◽  
Ana M. Sebastião ◽  
Cláudia A. Valente
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glial Cells ◽  
Neurofibrillary Tangles ◽  
Nlrp3 Inflammasome ◽  
Neuronal Death ◽  
Inflammatory Responses ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Wide Range

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease commonly diagnosed among the elderly population. AD is characterized by the loss of synaptic connections, neuronal death, and progressive cognitive impairment, attributed to the extracellular accumulation of senile plaques, composed by insoluble aggregates of amyloid-β (Aβ) peptides, and to the intraneuronal formation of neurofibrillary tangles shaped by hyperphosphorylated filaments of the microtubule-associated protein tau. However, evidence showed that chronic inflammatory responses, with long-lasting exacerbated release of proinflammatory cytokines by reactive glial cells, contribute to the pathophysiology of the disease. NLRP3 inflammasome (NLRP3), a cytosolic multiprotein complex sensor of a wide range of stimuli, was implicated in multiple neurological diseases, including AD. Herein, we review the most recent findings regarding the involvement of NLRP3 in the pathogenesis of AD. We address the mechanisms of NLRP3 priming and activation in glial cells by Aβ species and the potential role of neurofibrillary tangles and extracellular vesicles in disease progression. Neuronal death by NLRP3-mediated pyroptosis, driven by the interneuronal tau propagation, is also discussed. We present considerable evidence to claim that NLRP3 inhibition, is undoubtfully a potential therapeutic strategy for AD.

scholarly journals Application of optogenetic Amyloid-β distinguishes between metabolic and physical damages in neurodegeneration

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Chu Hsien Lim ◽  
Prameet Kaur ◽  
Emelyne Teo ◽  
Vanessa Yuk Man Lam ◽  
Fangchen Zhu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Progression ◽  
Biological Effects ◽  
Amyloid Β ◽  
Tissue Loss ◽  
Amyloid Β Peptide ◽  
Physical Damage ◽  
Living Tissues

The brains of Alzheimer’s disease patients show a decrease in brain mass and a preponderance of extracellular Amyloid-β plaques. These plaques are formed by aggregation of polypeptides that are derived from the Amyloid Precursor Protein (APP). Amyloid-β plaques are thought to play either a direct or an indirect role in disease progression, however the exact role of aggregation and plaque formation in the aetiology of Alzheimer’s disease (AD) is subject to debate as the biological effects of soluble and aggregated Amyloid-β peptides are difficult to separate in vivo. To investigate the consequences of formation of Amyloid-β oligomers in living tissues, we developed a fluorescently tagged, optogenetic Amyloid-β peptide that oligomerizes rapidly in the presence of blue light. We applied this system to the crucial question of how intracellular Amyloid-β oligomers underlie the pathologies of A. We use Drosophila, C. elegans and D. rerio to show that, although both expression and induced oligomerization of Amyloid-β were detrimental to lifespan and healthspan, we were able to separate the metabolic and physical damage caused by light-induced Amyloid-β oligomerization from Amyloid-β expression alone. The physical damage caused by Amyloid-β oligomers also recapitulated the catastrophic tissue loss that is a hallmark of late AD. We show that the lifespan deficit induced by Amyloid-β oligomers was reduced with Li+ treatment. Our results present the first model to separate different aspects of disease progression.

scholarly journals Elevated Expression of MiR-17 in Microglia of Alzheimer’s Disease Patients Abrogates Autophagy-Mediated Amyloid-β Degradation

2021 ◽  
Vol 12 ◽  
Author(s):  
Shady Estfanous ◽  
Kylene P. Daily ◽  
Mostafa Eltobgy ◽  
Nicholas P. Deems ◽  
Midhun N. K. Anne ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Therapeutic Interventions ◽  
Tissue Sections ◽  
Cargo Receptor ◽  
5Xfad Mouse ◽  
Aβ Degradation

Autophagy is a proposed route of amyloid-β (Aβ) clearance by microglia that is halted in Alzheimer’s Disease (AD), though mechanisms underlying this dysfunction remain elusive. Here, primary microglia from adult AD (5xFAD) mice were utilized to demonstrate that 5xFAD microglia fail to degrade Aβ and express low levels of autophagy cargo receptor NBR1. In 5xFAD mouse brains, we show for the first time that AD microglia express elevated levels of microRNA cluster Mirc1/Mir17-92a, which is known to downregulate autophagy proteins. By in situ hybridization in post-mortem AD human tissue sections, we observed that the Mirc1/Mir17-92a cluster member miR-17 is also elevated in human AD microglia, specifically in the vicinity of Aβ deposits, compared to non-disease controls. We show that NBR1 expression is negatively correlated with expression of miR-17 in human AD microglia via immunohistopathologic staining in human AD brain tissue sections. We demonstrate in healthy microglia that autophagy cargo receptor NBR1 is required for Aβ degradation. Inhibiting elevated miR-17 in 5xFAD mouse microglia improves Aβ degradation, autophagy, and NBR1 puncta formation in vitro and improves NBR1 expression in vivo. These findings offer a mechanism behind dysfunctional autophagy in AD microglia which may be useful for therapeutic interventions aiming to improve autophagy function in AD.

scholarly journals The relationship between cortical microstructural changes and in vivo amyloid‐β and tau in aging and preclinical Alzheimer's disease

2020 ◽  
Vol 16 (S4) ◽  
Author(s):  
Elena Rodriguez‐Vieitez ◽  
Victor Montal ◽  
Jorge Sepulcre ◽  
Cristina Lois ◽  
Bernard Hanseeuw ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Preclinical Alzheimer’S Disease ◽  
Microstructural Changes ◽  
The Relationship

scholarly journals The inhibition of cellular toxicity of amyloid-β by dissociated transthyretin

2020 ◽  
Vol 295 (41) ◽  
pp. 14015-14024 ◽  
Author(s):  
Qin Cao ◽  
Daniel H. Anderson ◽  
Wilson Y. Liang ◽  
Joshua Chou ◽  
Lorena Saelices
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protective Effect ◽  
Amyloid Β ◽  
Inhibitory Effect ◽  
Aβ Oligomers ◽  
Cellular Toxicity ◽  
Computational Docking

The protective effect of transthyretin (TTR) on cellular toxicity of β-amyloid (Aβ) has been previously reported. TTR is a tetrameric carrier of thyroxine in blood and cerebrospinal fluid, the pathogenic aggregation of which causes systemic amyloidosis. However, studies have documented a protective effect of TTR against cellular toxicity of pathogenic Aβ, a protein associated with Alzheimer's disease. TTR binds Aβ, alters its aggregation, and inhibits its toxicity both in vitro and in vivo. In this study, we investigate whether the amyloidogenic ability of TTR and its antiamyloid inhibitory effect are associated. Using protein aggregation and cytotoxicity assays, we found that the dissociation of the TTR tetramer, required for its amyloid pathogenesis, is also necessary to prevent cellular toxicity from Aβ oligomers. These findings suggest that the Aβ-binding site of TTR may be hidden in its tetrameric form. Aided by computational docking and peptide screening, we identified a TTR segment that is capable of altering Aβ aggregation and toxicity, mimicking TTR cellular protection. EM, immune detection analysis, and assessment of aggregation and cytotoxicity revealed that the TTR segment inhibits Aβ oligomer formation and also promotes the formation of nontoxic, nonamyloid amorphous aggregates, which are more sensitive to protease digestion. Finally, this segment also inhibits seeding of Aβ catalyzed by Aβ fibrils extracted from the brain of an Alzheimer's patient. Together, these findings suggest that mimicking the inhibitory effect of TTR with peptide-based therapeutics represents an additional avenue to explore for the treatment of Alzheimer's disease.

Associations of Neprilysin Activity in CSF with Biomarkers for Alzheimer’s Disease

2019 ◽  
Vol 19 (1) ◽  
pp. 43-50 ◽  
Author(s):  
Timo Grimmer ◽  
Oliver Goldhardt ◽  
Igor Yakushev ◽  
Marion Ortner ◽  
Christian Sorg ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Fdg Pet ◽  
Amyloid Β ◽  
Neuronal Injury ◽  
Pittsburgh Compound B ◽  
Positron Emission ◽  
Amyloid Load ◽  
Alzheimer’S Pathology

Background: Neprilysin (NEP) cleaves amyloid-β 1–42 (Aβ42) in the brain. Hence, we aimed to elucidate the effect of NEP on Aβ42 in cerebrospinal fluid (CSF) and on in vivo brain amyloid load using amyloid positron emission tomography (PET) with [11C]PiB (Pittsburgh compound B). In addition, associations with the biomarkers for neuronal injury, CSF-tau and FDG-PET, were investigated. Methods: Associations were calculated using global and voxel-based (SPM8) linear regression analyses in the same cohort of 23 highly characterized Alzheimer’s disease patients. Results: CSF-NEP was significantly inversely associated with CSF-Aβ42 and positively with the extent of neuronal injury as measured by CSF-tau and FDG-PET. Conclusions: Our results on CSF-NEP are compatible with the assumption that local degradation, amongst other mechanisms of amyloid clearance, plays a role in the development of Alzheimer’s pathology. In addition, CSF-NEP is associated with the extent and the rate of neurodegeneration.

scholarly journals N,N′-Diacetyl-p-phenylenediamine restores microglial phagocytosis and improves cognitive defects in Alzheimer’s disease transgenic mice

2019 ◽  
Vol 116 (47) ◽  
pp. 23426-23436 ◽  
Author(s):  
Min Hee Park ◽  
Misun Lee ◽  
Geewoo Nam ◽  
Mingeun Kim ◽  
Juhye Kang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Amyloid Β ◽  
Causative Factor ◽  
Central Feature ◽  
Microglial Phagocytosis ◽  
Cognitive Defects

As a central feature of neuroinflammation, microglial dysfunction has been increasingly considered a causative factor of neurodegeneration implicating an intertwined pathology with amyloidogenic proteins. Herein, we report the smallest synthetic molecule (N,N′-diacetyl-p-phenylenediamine [DAPPD]), simply composed of a benzene ring with 2 acetamide groups at the para position, known to date as a chemical reagent that is able to promote the phagocytic aptitude of microglia and subsequently ameliorate cognitive defects. Based on our mechanistic investigations in vitro and in vivo, 1) the capability of DAPPD to restore microglial phagocytosis is responsible for diminishing the accumulation of amyloid-β (Aβ) species and significantly improving cognitive function in the brains of 2 types of Alzheimer’s disease (AD) transgenic mice, and 2) the rectification of microglial function by DAPPD is a result of its ability to suppress the expression of NLRP3 inflammasome-associated proteins through its impact on the NF-κB pathway. Overall, our in vitro and in vivo investigations on efficacies and molecular-level mechanisms demonstrate the ability of DAPPD to regulate microglial function, suppress neuroinflammation, foster cerebral Aβ clearance, and attenuate cognitive deficits in AD transgenic mouse models. Discovery of such antineuroinflammatory compounds signifies the potential in discovering effective therapeutic molecules against AD-associated neurodegeneration.

Transfer of a healthy microbiota reduces amyloid and tau pathology in an Alzheimer’s disease animal model

Gut ◽  
2019 ◽  
Vol 69 (2) ◽  
pp. 283-294 ◽  
Author(s):  
Min-Soo Kim ◽  
Yoonhee Kim ◽  
Hyunjung Choi ◽  
Woojin Kim ◽  
Sumyung Park ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gut Microbiota ◽  
Neurofibrillary Tangles ◽  
Immune Cell ◽  
Amyloid Β ◽  
Memory Deficits ◽  
Faecal Microbiota ◽  
Inflammatory Monocytes ◽  
The Impact

ObjectiveCerebral amyloidosis and severe tauopathy in the brain are key pathological features of Alzheimer’s disease (AD). Despite a strong influence of the intestinal microbiota on AD, the causal relationship between the gut microbiota and AD pathophysiology is still elusive.DesignUsing a recently developed AD-like pathology with amyloid and neurofibrillary tangles (ADLPAPT) transgenic mouse model of AD, which shows amyloid plaques, neurofibrillary tangles and reactive gliosis in their brains along with memory deficits, we examined the impact of the gut microbiota on AD pathogenesis.ResultsComposition of the gut microbiota in ADLPAPT mice differed from that of healthy wild-type (WT) mice. Besides, ADLPAPT mice showed a loss of epithelial barrier integrity and chronic intestinal and systemic inflammation. Both frequent transfer and transplantation of the faecal microbiota from WT mice into ADLPAPT mice ameliorated the formation of amyloid β plaques and neurofibrillary tangles, glial reactivity and cognitive impairment. Additionally, the faecal microbiota transfer reversed abnormalities in the colonic expression of genes related to intestinal macrophage activity and the circulating blood inflammatory monocytes in the ADLPAPT recipient mice.ConclusionThese results indicate that microbiota-mediated intestinal and systemic immune aberrations contribute to the pathogenesis of AD in ADLPAPT mice, providing new insights into the relationship between the gut (colonic gene expression, gut permeability), blood (blood immune cell population) and brain (pathology) axis and AD (memory deficits). Thus, restoring gut microbial homeostasis may have beneficial effects on AD treatment.

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