scholarly journals Analysis of Age-Dependent Alterations in Excitability Properties of CA1 Pyramidal Neurons in an APPPS1 Model of Alzheimer’s Disease

2021 ◽  
Vol 13 ◽  
Author(s):  
Paola Vitale ◽  
Ana Rita Salgueiro-Pereira ◽  
Carmen Alina Lupascu ◽  
Michael Willem ◽  
Rosanna Migliore ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Pyramidal Neuron ◽  
Amyloid Β ◽  
Clear Correlation ◽  
Neuron Excitability ◽  
Model Of Alzheimer’S Disease ◽  
Age Dependent ◽  
Ca1 Pyramidal Neuron

Age-dependent accumulation of amyloid-β, provoking increasing brain amyloidopathy, triggers abnormal patterns of neuron activity and circuit synchronization in Alzheimer’s disease (AD) as observed in human AD patients and AD mouse models. Recent studies on AD mouse models, mimicking this age-dependent amyloidopathy, identified alterations in CA1 neuron excitability. However, these models generally also overexpress mutated amyloid precursor protein (APP) and presenilin 1 (PS1) and there is a lack of a clear correlation of neuronal excitability alterations with progressive amyloidopathy. The active development of computational models of AD points out the need of collecting such experimental data to build a reliable disease model exhibiting AD-like disease progression. We therefore used the feature extraction tool of the Human Brain Project (HBP) Brain Simulation Platform to systematically analyze the excitability profile of CA1 pyramidal neuron in the APPPS1 mouse model. We identified specific features of neuron excitability that best correlate either with over-expression of mutated APP and PS1 or increasing Aβ amyloidopathy. Notably, we report strong alterations in membrane time constant and action potential width and weak alterations in firing behavior. Also, using a CA1 pyramidal neuron model, we evidence amyloidopathy-dependent alterations in Ih. Finally, cluster analysis of these recordings showed that we could reliably assign a trace to its correct group, opening the door to a more refined, less variable analysis of AD-affected neurons. This inter-disciplinary analysis, bringing together experimentalists and modelers, helps to further unravel the neuronal mechanisms most affected by AD and to build a biologically plausible computational model of the AD brain.

scholarly journals Neural oscillations during cognitive processes in an App knock-in mouse model of Alzheimer’s disease pathology

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Sofia Jacob ◽  
Gethin Davies ◽  
Marijke De Bock ◽  
Bart Hermans ◽  
Cindy Wintmolders ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Home Environment ◽  
Amyloid Β ◽  
Wild Type ◽  
Model Of Alzheimer’S Disease ◽  
Age Dependent ◽  
In The Wild ◽  
Phase Amplitude

Abstract Multiple animal models have been created to gain insight into Alzheimer’s disease (AD) pathology. Among the most commonly used models are transgenic mice overexpressing human amyloid precursor protein (APP) with mutations linked to familial AD, resulting in the formation of amyloid β plaques, one of the pathological hallmarks observed in AD patients. However, recent evidence suggests that the overexpression of APP by itself can confound some of the reported observations. Therefore, we investigated in the present study the AppNL-G-Fmodel, an App knock-in (App-KI) mouse model that develops amyloidosis in the absence of APP-overexpression. Our findings at the behavioral, electrophysiological, and histopathological level confirmed an age-dependent increase in Aβ1–42 levels and plaque deposition in these mice in accordance with previous reports. This had apparently no consequences on cognitive performance in a visual discrimination (VD) task, which was largely unaffected in AppNL-G-F mice at the ages tested. Additionally, we investigated neurophysiological functioning of several brain areas by phase-amplitude coupling (PAC) analysis, a measure associated with adequate cognitive functioning, during the VD task (starting at 4.5 months) and the exploration of home environment (at 5 and 8 months of age). While we did not detect age-dependent changes in PAC during home environment exploration for both the wild-type and the AppNL-G-F mice, we did observe subtle changes in PAC in the wild-type mice that were not present in the AppNL-G-F mice.

scholarly journals Loss of Hippocampal Calretinin and Parvalbumin Interneurons in the 5XFAD Mouse Model of Alzheimer’s Disease

ASN NEURO ◽  
2020 ◽  
Vol 12 ◽  
pp. 175909142092535 ◽  
Author(s):  
Naomi K. Giesers ◽  
Oliver Wirths
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Calcium Binding ◽  
Neuronal Degeneration ◽  
Disease Process ◽  
Amyloid Β ◽  
Gamma Aminobutyric Acid ◽  
Wild Type ◽  
Model Of Alzheimer’S Disease

The deposition of amyloid-β peptides in the form of extracellular plaques and neuronal degeneration belong to the hallmark features of Alzheimer’s disease (AD). In addition, impaired calcium homeostasis and altered levels in calcium-binding proteins seem to be associated with the disease process. In this study, calretinin- (CR) and parvalbumin- (PV) positive gamma-aminobutyric acid-producing (GABAergic) interneurons were quantified in different hippocampal subfields of 12-month-old wild-type mice, as well as in the transgenic AD mouse models 5XFAD and Tg4-42. While, in comparison with wild-type mice, CR-positive interneurons were mainly reduced in the CA1 and CA2/3 regions in plaque-bearing 5XFAD mice, PV-positive interneurons were reduced in all analyzed subfields including the dentate gyrus. No reduction in CR- and PV-positive interneuron numbers was detected in the non-plaque-forming Tg4-42 mouse, although this model has been previously demonstrated to harbor a massive loss of CA1 pyramidal neurons. These results provide information about hippocampal interneuron numbers in two relevant AD mouse models, suggesting that interneuron loss in this brain region may be related to extracellular amyloid burden.

scholarly journals Induced Pluripotent Stem Cell-Derived Neural Precursors Improve Memory, Synaptic and Pathological Abnormalities in a Mouse Model of Alzheimer’s Disease

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1802
Author(s):  
Enrique Armijo ◽  
George Edwards ◽  
Andrea Flores ◽  
Jorge Vera ◽  
Mohammad Shahnawaz ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Symptoms ◽  
Memory Loss ◽  
Amyloid Β ◽  
Cerebral Atrophy ◽  
Brain Inflammation ◽  
Neural Precursors ◽  
Model Of Alzheimer’S Disease ◽  
Induced Pluripotent

Alzheimer’s disease (AD) is the most common type of dementia in the elderly population. The disease is characterized by progressive memory loss, cerebral atrophy, extensive neuronal loss, synaptic alterations, brain inflammation, extracellular accumulation of amyloid-β (Aβ) plaques, and intracellular accumulation of hyper-phosphorylated tau (p-tau) protein. Many recent clinical trials have failed to show therapeutic benefit, likely because at the time in which patients exhibit clinical symptoms the brain is irreversibly damaged. In recent years, induced pluripotent stem cells (iPSCs) have been suggested as a promising cell therapy to recover brain functionality in neurodegenerative diseases such as AD. To evaluate the potential benefits of iPSCs on AD progression, we stereotaxically injected mouse iPSC-derived neural precursors (iPSC-NPCs) into the hippocampus of aged triple transgenic (3xTg-AD) mice harboring extensive pathological abnormalities typical of AD. Interestingly, iPSC-NPCs transplanted mice showed improved memory, synaptic plasticity, and reduced AD brain pathology, including a reduction of amyloid and tangles deposits. Our findings suggest that iPSC-NPCs might be a useful therapy that could produce benefit at the advanced clinical and pathological stages of AD.

Gut Microbiota Alterations and Cognitive Impairment Are Sexually Dissociated in a Transgenic Mice Model of Alzheimer’s Disease

2021 ◽  
pp. 1-20
Author(s):  
Daniel Cuervo-Zanatta ◽  
Jaime Garcia-Mena ◽  
Claudia Perez-Cruz
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Gut Microbiota ◽  
Cognitive Skills ◽  
Amyloid Β ◽  
Short Chain Fatty Acids ◽  
Mice Model ◽  
Model Of Alzheimer’S Disease ◽  
Cognitive Deficiencies

Background: Normal aging is accompanied by cognitive deficiencies, affecting women and men equally. Aging is the main risk factor for Alzheimer’s disease (AD), with women having a higher risk. The higher prevalence of AD in women is associated with the abrupt hormonal decline seen after menopause. However, other factors may be involved in this sex-related cognitive decline. Alterations in gut microbiota (GM) and its bioproducts have been reported in AD subjects and transgenic (Tg) mice, having a direct impact on brain amyloid-β pathology in male (M), but not in female (F) mice. Objective: The aim of this work was to determine GM composition and cognitive dysfunction in M and F wildtype (WT) and Tg mice, in a sex/genotype segregation design. Methods: Anxiety, short term working-memory, spatial learning, and long-term spatial memory were evaluated in 6-month-old WT and Tg male mice. Fecal short chain fatty acids were determined by chromatography, and DNA sequencing and bioinformatic analyses were used to determine GM differences. Results: We observed sex-dependent differences in cognitive skills in WT mice, favoring F mice. However, the cognitive advantage of females was lost in Tg mice. GM composition showed few sex-related differences in WT mice. Contrary, Tg-M mice presented a more severe dysbiosis than Tg-F mice. A decreased abundance of Ruminococcaceae was associated with cognitive deficits in Tg-F mice, while butyrate levels were positively associated with better working- and object recognition-memory in WT-F mice. Conclusion: This report describes a sex-dependent association between GM alterations and cognitive impairment in a mice model of AD.

Astrocyte Reactivity in Alzheimer’s Disease: Therapeutic Opportunities to Promote Repair

2021 ◽  
Vol 18 ◽  
Author(s):  
Nazanin Mirzaei ◽  
Nicola Davis ◽  
Tsz Wing Chau ◽  
Magdalena Sastre
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Mouse Models ◽  
Neurodegenerative Disorders ◽  
Amyloid Β ◽  
Neuroprotective Effects ◽  
Synaptic Density ◽  
Inflammatory Profile

: Astrocytes are fast climbing the ladder of importance in neurodegenerative disorders, particularly in Alzheimer’s disease (AD), with the prominent presence of reactive astrocytes sur- rounding amyloid β- plaques, together with activated microglia. Reactive astrogliosis, implying morphological and molecular transformations in astrocytes, seems to precede neurodegeneration, suggesting a role in the development of the disease. Single-cell transcriptomics has recently demon- strated that astrocytes from AD brains are different from “normal” healthy astrocytes, showing dys- regulations in areas such as neurotransmitter recycling, including glutamate and GABA, and im- paired homeostatic functions. However, recent data suggest that the ablation of astrocytes in mouse models of amyloidosis results in an increase in amyloid pathology as well as in the inflammatory profile and reduced synaptic density, indicating that astrocytes mediate neuroprotective effects. The idea that interventions targeting astrocytes may have great potential for AD has therefore emerged, supported by a range of drugs and stem cell transplantation studies that have successfully shown a therapeutic effect in mouse models of AD. In this article, we review the latest reports on the role and profile of astrocytes in AD brains and how manipulation of astrocytes in animal mod- els has paved the way for the use of treatments enhancing astrocytic function as future therapeutic avenues for AD.

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