scholarly journals An Overview of Astrocyte Responses in Genetically Induced Alzheimer’s Disease Mouse Models

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2415
Author(s):  
Fokion Spanos ◽  
Shane A. Liddelow
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Cell Types ◽  
Functional Changes ◽  
New Methods ◽  
Metabolic Functions ◽  
The Central Nervous System ◽  
Multiple Cell ◽  
The Many

Alzheimer’s disease (AD) is the most common form of dementia. Despite many years of intense research, there is currently still no effective treatment. Multiple cell types contribute to disease pathogenesis, with an increasing body of data pointing to the active participation of astrocytes. Astrocytes play a pivotal role in the physiology and metabolic functions of neurons and other cells in the central nervous system. Because of their interactions with other cell types, astrocyte functions must be understood in their biologic context, thus many studies have used mouse models, of which there are over 190 available for AD research. However, none appear able to fully recapitulate the many functional changes in astrocytes reported in human AD brains. Our review summarizes the observations of astrocyte biology noted in mouse models of familial and sporadic AD. The limitations of AD mouse models will be discussed and current attempts to overcome these disadvantages will be described. With increasing understanding of the non-neuronal contributions to disease, the development of new methods and models will provide further insights and address important questions regarding the roles of astrocytes and other non-neuronal cells in AD pathophysiology. The next decade will prove to be full of exciting opportunities to address this devastating disease.

scholarly journals TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models

2015 ◽  
Vol 212 (3) ◽  
pp. 287-295 ◽  
Author(s):  
Taylor R. Jay ◽  
Crystal M. Miller ◽  
Paul J. Cheng ◽  
Leah C. Graham ◽  
Shane Bemiller ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
High Risk ◽  
Mouse Models ◽  
Myeloid Cells ◽  
Cell Types ◽  
Targeted Therapeutics ◽  
Amyloid Deposits ◽  
Inflammatory Macrophages

Variants in triggering receptor expressed on myeloid cells 2 (TREM2) confer high risk for Alzheimer’s disease (AD) and other neurodegenerative diseases. However, the cell types and mechanisms underlying TREM2’s involvement in neurodegeneration remain to be established. Here, we report that TREM2 is up-regulated on myeloid cells surrounding amyloid deposits in AD mouse models and human AD tissue. TREM2 was detected on CD45hiLy6C+ myeloid cells, but not on P2RY12+ parenchymal microglia. In AD mice deficient for TREM2, the CD45hiLy6C+ macrophages are virtually eliminated, resulting in reduced inflammation and ameliorated amyloid and tau pathologies. These data suggest a functionally important role for TREM2+ macrophages in AD pathogenesis and an unexpected, detrimental role of TREM2 in AD pathology. These findings have direct implications for future development of TREM2-targeted therapeutics.

Acetylcholinesterase Enzyme Inhibitor Molecules with Therapeutic Potential for Alzheimer's Disease

2021 ◽  
Vol 20 ◽  
Author(s):  
Bhuvaneswari Siwaraman ◽  
Vijaykumar R. ◽  
Bala Aakash Velmurugan ◽  
Ramalakshmi Natarajan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Enzyme Inhibitor ◽  
Therapeutic Potential ◽  
Psychological Symptoms ◽  
Heteroaromatic Compounds ◽  
The Central Nervous System ◽  
The Many ◽  
Acetylcholinesterase Enzyme ◽  
Ellman’S Method

: Acetylcholinesterase (AchE), hydrolase enzyme, regulates the hydrolysis of acetylcholine neurotransmitter in the neurons. AchE is found majorly in the central nervous system at the site of cholinergic neurotransmission. It is involved in the pathophysiology of Alzheimer’s disease-causing dementia, cognitive impairment, behavioral and psychological symptoms. Recent findings involved the inhibition of AchE that could aid in the treatment of Alzheimer's. Many drugs of different classes being analyzed in the clinical trials and examined for their potency. Drugs that are used in the treatment of Alzheimer’s disease are donepezil, galantamine, tacrine, rivastigmine shows major adverse effects. To overcome this, researchers work on novel drugs to elicit inhibition. This review comprises the many hybrids and non-hybrid forms of heteroaromatic and non-heteroaromatic compounds that were designed and evaluated for AchE inhibition by Ellman’s method of assay. These novel compounds may assist the future perspectives in the discovery of novel moieties against Alzheimer’s disease by the inhibition of AchE.

Retinal Changes in Transgenic Mouse Models of Alzheimer’s Disease

2021 ◽  
Vol 18 ◽  
Author(s):  
Li Guo ◽  
Nivedita Ravindran ◽  
Daniel Hill ◽  
M. Francesca Cordeiro
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Neurodegenerative Disorder ◽  
Neuronal Loss ◽  
Immunohistochemical Analysis ◽  
Therapeutic Effects ◽  
The Central Nervous System ◽  
New Treatments ◽  
The Brain

: Alzheimer’s disease (AD) is a neurodegenerative disorder, the most common form of dementia. AD is characterized by amyloid-ß (Aß) plaques and neurofibrillary tangles (NFT) in the brain, in association with neuronal loss and synaptic failure, causing cognitive deficits. Accurate and early diagnosis is currently unavailable in lifespan, hampering early intervention of potential new treatments. Visual deficits have been well-documented in AD patients, and the pathological changes identified in the brain are also believed to be found in the retina, an integral part of the central nervous system. Retinal changes can be detected by real-time non-invasive imaging due to the transparent nature of the ocular media, potentially allowing an earlier diagnosis as well as monitoring disease progression and treatment outcome. Animal models are essential for AD research, and this review has a focus on retinal changes in various transgenic AD mouse models with retinal imaging and immunohistochemical analysis as well as therapeutic effects in those models. We also discuss the limitations of transgenic AD models in clinical translations.

scholarly journals Type I interferon (IFN)-inducible Absent in Melanoma 2 proteins in neuroinflammation: implications for Alzheimer’s disease

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Divaker Choubey
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Types ◽  
Type I ◽  
Innate Immune Responses ◽  
The Central Nervous System ◽  
Anti Inflammatory ◽  
Species Specific

AbstractCumulative evidence indicates that activation of innate immune responses in the central nervous system (CNS) induces the expression of type 1 interferons (T1 IFNs), a family of cytokines. The T1 IFNs (IFN-α/β), through activation of the JAK/STAT-signaling in microglia, astrocytes, and neurons, induce the expression of IFN-inducible proteins, which mediate the pro- and anti-inflammatory functions of IFNs. Accordingly, T1 IFN-inducible Absent in Melanoma 2 proteins (murine Aim2 and human AIM2) negatively regulate the expression of TI IFNs and, upon sensing higher levels of cytosolic DNA, assemble the Aim2/AIM2 inflammasome, resulting in activation of caspase-1, pyroptosis, and the secretion of pro-inflammatory cytokines (e.g., IL-1β and IL-18). Of interest, studies have indicated a role for the Aim2/AIM2 proteins in neuroinflammation and neurodegenerative diseases, including Alzheimer’s disease (AD). The ability of Aim2/AIM2 proteins to exert pro- and anti-inflammatory effects in CNS may depend upon age, sex hormones, cell-types, and the expression of species-specific negative regulators of the Aim2/AIM2 inflammasome. Therefore, we discuss the role of Aim2/AIM2 proteins in the development of AD. An improved understanding of the role of Absent in Melanoma 2 proteins in AD could identify new approaches to treat patients.

scholarly journals Transcriptional Networks of Microglia in Alzheimer’s Disease and Insights into Pathogenesis

Genes ◽  
2019 ◽  
Vol 10 (10) ◽  
pp. 798 ◽  
Author(s):  
Chew ◽  
Petretto
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transcriptional Profiling ◽  
Cell Types ◽  
Transcriptional Networks ◽  
Network Analyses ◽  
The Central Nervous System ◽  
Mapping Gene ◽  
Transcriptomic Studies

Microglia, the main immune cells of the central nervous system, are increasingly implicated in Alzheimer’s disease (AD). Manifold transcriptomic studies in the brain have not only highlighted microglia’s role in AD pathogenesis, but also mapped crucial pathological processes and identified new therapeutic targets. An important component of many of these transcriptomic studies is the investigation of gene expression networks in AD brain, which has provided important new insights into how coordinated gene regulatory programs in microglia (and other cell types) underlie AD pathogenesis. Given the rapid technological advancements in transcriptional profiling, spanning from microarrays to single-cell RNA sequencing (scRNA-seq), tools used for mapping gene expression networks have evolved to keep pace with the unique features of each transcriptomic platform. In this article, we review the trajectory of transcriptomic network analyses in AD from brain to microglia, highlighting the corresponding methodological developments. Lastly, we discuss examples of how transcriptional network analysis provides new insights into AD mechanisms and pathogenesis.

scholarly journals Generation of APOE knock-down SK-N-SH human neuroblastoma cells using CRISPR/Cas9: a novel cellular model relevant to Alzheimer’s disease research

2021 ◽  
Vol 41 (2) ◽  
Author(s):  
Sonia Sanz Muñoz ◽  
Brett Garner ◽  
Lezanne Ooi
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuroblastoma Cells ◽  
Cell Types ◽  
Human Neuroblastoma ◽  
Multiple Cell ◽  
Fragmentation Patterns ◽  
The Brain ◽  
Precise Role ◽  
Apoe Expression

Abstract APOE ε4 is the major genetic risk factor for Alzheimer’s disease (AD). A precise role for apolipoprotein E (apoE) in the pathogenesis of the disease remains unclear in part due to its expression in multiple cell types of the brain. APOE is highly expressed in astrocytes and microglia, however its expression can also be induced in neurons under various conditions. The neuron-like cell line SK-N-SH is a useful model in the study of the cellular and molecular effects of apoE as it can be differentiated with retinoic acid to express and secrete high levels of apoE and it also shows the same apoE fragmentation patterns observed in the human brain. We previously found that apoE is cleaved into a 25-kDa fragment by high temperature-requirement serine protease A1 (HtrA1) in SK-N-SH cells. To further understand the endogenous functions of apoE, we used CRISPR/Cas9 to generate SK-N-SH cell lines with APOE expression knocked-down (KD). APOE KD cells showed lower APOE and HTRA1 expression than parental SK-N-SH cells but no overt differences in neuritogenesis or cell proliferation compared with the CRISPR/Cas9 control cells. This research shows that the loss of apoE and HtrA1 has a negligible effect on neuritogenesis and cell survival in SK-N-SH neuron-like cells.

The Blood brain-barrier and its role in Alzheimer’s disease

Neuroforum ◽  
2018 ◽  
Vol 24 (4) ◽  
pp. A197-A205 ◽  
Author(s):  
Steffen E. Storck ◽  
Claus U. Pietrzik
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Brain Barrier ◽  
Cell Types ◽  
Brain Barrier ◽  
Blood Brain ◽  
The Central Nervous System ◽  
Different Cell Types ◽  
The Brain ◽  
Brain Homeostasis

Abstract The blood brain-barrier (BBB), built up by the interaction of different cell types in vessels of the brain, is essential for brain homeostasis. As a gatekeeper of the central nervous system (CNS), the BBB controls the exchange of molecules between brain and blood. In many neurodegenerative diseases including Alzheimer’s disease (AD) the BBB show alterations which impair brain function and promote neurodegeneration. As an important elimination route for neurotoxic amyloid-beta (Aβ), the BBB is crucial for the healthy brain by regulating the concentration of soluble Aβ in the interstitial fluid (ISF) in the brain. Here, we discuss the composition and distinctive physiological features of CNS vasculature and the pathological alterations that are present in AD and disturb BBB function.

scholarly journals Disease specific alterations in the olfactory mucosa of patients with Alzheimer’s disease

2020 ◽  
Author(s):  
Riikka Lampinen ◽  
Mohammad Feroze Fazaludeen ◽  
Simone Avesani ◽  
Tiit Örd ◽  
Elina Penttilä ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Expression Patterns ◽  
Cell Types ◽  
Olfactory Mucosa ◽  
Specific Gene ◽  
Cellular Mechanisms ◽  
Distinct Cell ◽  
Inflammatory Processes ◽  
Multiple Cell

ABSTRACTOlfactory dysfunction manifests in early stages of neurodegeneration in several disorders of the central nervous system. The sense of smell is orchestrated by the cells of the olfactory mucosa located in the upper nasal cavity, however, it is unclear how this tissue reflects key neurodegenerative features in Alzheimer’s disease (AD). Here we report that olfactory mucosa (OM) cells of patients with AD secrete increased amounts of toxic amyloid-beta. We detail cell-type specific gene expression patterns, unveiling 154 differentially expressed AD-associated genes compared to the cognitively normal controls, and 5 distinct cell populations in the cultures, together with disease-associated subpopulations. Overall, coordinated alteration of RNA and protein metabolism, inflammatory processes and signal transduction were observed in multiple cell types, suggesting a key role in AD pathophysiology. Our results demonstrate the potential of OM cultures as a new cellular model for AD. Moreover, for the first time we provide single cell transcript data for investigating the molecular and cellular mechanisms of AD in the OM.

Paired helical filaments (PHF) in rats: An experimental animal model for Alzheimer's disease

1987 ◽  
Vol 45 ◽  
pp. 842-843
Author(s):  
V.J.A. Montpetit ◽  
S. Dancea ◽  
S.W. French ◽  
D.F. Clapin
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Model ◽  
Paired Helical Filaments ◽  
Ethanol Intoxication ◽  
Drg Neurons ◽  
Critical Difference ◽  
Suitable Animal Model ◽  
The Central Nervous System ◽  
Chronic Ethanol Intoxication

A continuing problem in Alzheimer research is the lack of a suitable animal model for the disease. The absence of neurofibrillary tangles of paired helical filaments is the most critical difference in the processes by which the central nervous system ages in most species other than man. However, restricting consideration to single phenomena, one may identify animal models for specific aspects of Alzheimer's disease. Abnormal fibers resembling PHF have been observed in dorsal root ganglia (DRG) neurons of rats in a study of chronic ethanol intoxication and spontaneously in aged rats. We present in this report evidence that PHF-like filaments occur in ethanol-treated rats of young age. In control animals lesions similar in some respects to our observations of cytoskeletal pathology in pyridoxine induced neurotoxicity were observed.Male Wistar BR rats (Charles River Labs) weighing 350 to 400 g, were implanted with a single gastrostomy cannula and infused with a liquid diet containing 30% of total calories as fat plus ethanol or isocaloric dextrose.

Sign in / Sign up

Export Citation Format

Share Document