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 A fragment of cell adhesion molecule L1 reduces amyloid-β plaques in a mouse model of Alzheimer’s disease

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Junkai Hu ◽  
Stanley Li Lin ◽  
Melitta Schachner
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Adhesion ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Transforming Growth Factor ◽  
Amyloid Β ◽  
Wild Type ◽  
Model Of Alzheimer’S Disease ◽  
Cell Adhesion Molecule L1

AbstractDeposition of amyloid-β (Aβ) in the brain is one of the important histopathological features of Alzheimer’s disease (AD). Previously, we reported a correlation between cell adhesion molecule L1 (L1) expression and the occurrence of AD, but its relationship was unclear. Here, we report that the expression of L1 and a 70 kDa cleavage product of L1 (L1-70) was reduced in the hippocampus of AD (APPswe) mice. Interestingly, upregulation of L1-70 expression in the hippocampus of 18-month-old APPswe mice, by parabiosis involving the joining of the circulatory system of an 18-month-old APPswe mouse with a 2-month-old wild-type C57BL/6 mouse, reduced amyloid plaque deposition. Furthermore, the reduction was accompanied by the appearance of a high number of activated microglia. Mechanistically, we observed that L1-70 could combine with topoisomerase 1 (Top1) to form a complex, L1-70/Top1, that was able to regulate expression of macrophage migration inhibitory factor (MIF), resulting in the activation of microglia and reduction of Aβ plaques. Also, transforming growth factor β1 (TGFβ-1) transferred from the blood of young wild-type C57BL/6 mice to the aged AD mice, was identified as a circulating factor that induces full-length L1 and L1-70 expression. All together, these findings suggest that L1-70 contributes to the clearance of Aβ in AD, thereby adding a novel perspective in understanding AD pathogenesis.

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 Effects of GrandFusion Diet on Cognitive Impairment in Transgenic Mouse Model of Alzheimer’s Disease

Nutrients ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 117 ◽  
Author(s):  
Jin Yu ◽  
Hong Zhu ◽  
Saeid Taheri ◽  
William Mondy ◽  
Stephen Perry ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Cathepsin B ◽  
Memory Impairment ◽  
Chronic Traumatic Encephalopathy ◽  
Disease Process ◽  
Amyloid Β ◽  
Aβ Peptide ◽  
Model Of Alzheimer’S Disease

Alzheimer’s disease (AD) is the result of the deposition of amyloid β (Aβ) peptide into amyloid fibrils and tau into neurofibrillary tangles. At the present time, there are no possible treatments for the disease. We have recently shown that diets enriched in phytonutrients show protection or limit the extent of damage in a number of neurological disorders. GrandFusion (GF) diets have attenuated the outcomes in animal models of traumatic brain injury, cerebral ischemia, and chronic traumatic encephalopathy. In this study, we investigated the effect of GF diets in a mouse model of AD prior to the development of amyloid plaques to show how this treatment paradigm would alter the accumulation of Aβ peptide and related pathologic changes (i.e., inflammation, cathepsin B, and memory impairment). Administration of GF diets (2–4%) over a period of four months in APP/ΔPS1 double-transgenic mice resulted in attenuation in Aβ peptide levels, reduction of amyloid load, and inflammation, increased cathepsin B expression, and improved spatial orientation. Additionally, treatment with GF diets increased nerve growth factor (NGF) levels in the brain and tempered the memory impairment in the animal model. These data suggest that GF diets may alter the development and progression of the mechanisms associated with the disease process to effectively modify AD pathogenesis.

scholarly journals A conformation specific antibody against Oligomeric β-Amyloid Restores Neuronal Integrity in a Mouse Model of Alzheimer’s Disease

2020 ◽  
pp. jbc.RA120.015327
Author(s):  
Ping He ◽  
Philip Schulz ◽  
Michael R. Sierks
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Survival Rates ◽  
Amyloid Β ◽  
Critical Factor ◽  
Wild Type ◽  
Single Chain ◽  
Model Of Alzheimer’S Disease ◽  
Β Amyloid

Conformationally distinct aggregates of the Amyloid β (Aβ) peptide accumulate in brains of Alzheimer’s disease (AD) patients, but the roles of the different aggregates in disease progression are not clear. We previously isolated two single-chain variable domain antibody fragments (scFvs), C6T and A4, that selectively bind different toxic conformational variants of oligomeric Aβ. Here we utilize these scFvs to localize the presence of these Aβ variants in human AD brain and to demonstrate their potential as therapeutic agents for treating AD. Both A4 and C6T label oligomeric Aβ in extracellular amyloid plaques, while C6T also labels intracellular oligomeric Aβ in human AD brain tissue and in an AD mouse model. For therapeutic studies, the A4 and C6T scFvs were expressed in the AD mice by viral infection of liver cells.  The scFvs were administered at 2 months of age and mice sacrificed at 9 months.  The scFvs contained a peptide tag to facilitate transport across the blood brain barrier. While treatment with C6T only slightly decreased Aβ deposits and plaque-associated inflammation, it restored neuronal integrity to wild-type levels, significantly promoted growth of new neurons, and impressively rescued survival rates to wild type levels. Treatment with A4 on the other hand significantly decreased Aβ deposits, but did not significantly decrease neuroinflammation or promote neuronal integrity, neurogenesis or survival rate. These results suggest that the specific Aβ conformation targeted in therapeutic applications greatly affects the outcome, and the location of the targeted Aβ variants may also play a critical factor.

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 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.

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