Chronic GluN2B Antagonism Disrupts Behavior in Wild-Type Mice Without Protecting Against Synapse Loss or Memory Impairment in Alzheimer's Disease Mouse Models

Chronic sleep insufficiency is becoming a common issue in the young population nowadays, mostly due to life habits and work stress. Studies in animal models of neurological diseases reported that it would accelerate neurodegeneration progression and exacerbate interstitial metabolic waste accumulation in the brain. In this paper, we study whether chronic sleep insufficiency leads to neurodegenerative diseases in young wild-type animals without a genetic pre-disposition. To this aim, we modeled chronic sleep fragmentation (SF) in young wild-type mice. We detected pathological hyperphosphorylated-tau (Ser396/Tau5) and gliosis in the SF hippocampus. 18F-labeled fluorodeoxyglucose positron emission tomography scan (18F-FDG-PET) further revealed a significant increase in brain glucose metabolism, especially in the hypothalamus, hippocampus and amygdala. Hippocampal RNAseq indicated that immunological and inflammatory pathways were significantly altered in 1.5-month SF mice. More interestingly, differential expression gene lists from stress mouse models showed differential expression patterns between 1.5-month SF and control mice, while Alzheimer's disease, normal aging, and APOEε4 mutation mouse models did not exhibit any significant pattern. In summary, 1.5-month sleep fragmentation could generate AD-like pathological changes including tauopathy and gliosis, mainly linked to stress, as the incremented glucose metabolism observed with PET imaging suggested. Further investigation will show whether SF could eventually lead to chronic neurodegeneration if the stress condition is prolonged in time.

Download Full-text

Infusion of neural precursors improves memory impairment in mouse models of Alzheimer’s disease

Alzheimer s & Dementia ◽

10.1002/alz.046389 ◽

2020 ◽

Vol 16 (S9) ◽

Author(s):

Nazaret Gamez Ruiz ◽

Enrique Antonio Armijo Fuentes ◽

Ruben Gomez‐Gutierrez ◽

Claudio Soto ◽

Ines Moreno‐Gonzalez

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Models ◽

Memory Impairment ◽

Neural Precursors

Download Full-text

Neuronal and Astrocytic Extracellular Vesicle Biomarkers in Blood Reflect Brain Pathology in Mouse Models of Alzheimer’s Disease

Cells ◽

10.3390/cells10050993 ◽

2021 ◽

Vol 10 (5) ◽

pp. 993

Author(s):

Francheska Delgado-Peraza ◽

Carlos J. Nogueras-Ortiz ◽

Olga Volpert ◽

Dong Liu ◽

Edward J. Goetzl ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Models ◽

Extracellular Vesicle ◽

Strong Correlations ◽

Wild Type ◽

Total Tau ◽

Amyloid Aβ ◽

Β Amyloid ◽

Potential Use

Circulating neuronal extracellular vesicles (NEVs) of Alzheimer’s disease (AD) patients show high Tau and β-amyloid (Aβ) levels, whereas their astrocytic EVs (AEVs) contain high complement levels. To validate EV proteins as AD biomarkers, we immunocaptured NEVs and AEVs from plasma collected from fifteen wild type (WT), four 2xTg-AD, nine 5xFAD, and fifteen 3xTg-AD mice and assessed biomarker relationships with brain tissue levels. NEVs from 3xTg-AD mice had higher total Tau (p = 0.03) and p181-Tau (p = 0.0004) compared to WT mice. There were moderately strong correlations between biomarkers in NEVs and cerebral cortex and hippocampus (total Tau: cortex, r = 0.4, p = 0.009; p181-Tau: cortex, r = 0.7, p < 0.0001; hippocampus, r = 0.6, p < 0.0001). NEVs from 5xFAD compared to other mice had higher Aβ42 (p < 0.005). NEV Aβ42 had moderately strong correlations with Aβ42 in cortex (r = 0.6, p = 0.001) and hippocampus (r = 0.7, p < 0.0001). AEV C1q was elevated in 3xTg-AD compared to WT mice (p = 0.005); AEV C1q had moderate-strong correlations with C1q in cortex (r = 0.9, p < 0.0001) and hippocampus (r = 0.7, p < 0.0001). Biomarkers in circulating NEVs and AEVs reflect their brain levels across multiple AD mouse models supporting their potential use as a “liquid biopsy” for neurological disorders.

Download Full-text

Color and contrast vision in mouse models of aging and Alzheimer’s disease using a novel visual-stimuli four-arm maze

Scientific Reports ◽

10.1038/s41598-021-80988-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jean-Philippe Vit ◽

Dieu-Trang Fuchs ◽

Ariel Angel ◽

Aharon Levy ◽

Itschak Lamensdorf ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Contrast Sensitivity ◽

Mouse Models ◽

Exploratory Behavior ◽

Visual Stimuli ◽

Color Discrimination ◽

Murine Models ◽

Wild Type ◽

Contrast Vision

AbstractWe introduce a novel visual-stimuli four-arm maze (ViS4M) equipped with spectrally- and intensity-controlled LED emitters and dynamic grayscale objects that relies on innate exploratory behavior to assess color and contrast vision in mice. Its application to detect visual impairments during normal aging and over the course of Alzheimer’s disease (AD) is evaluated in wild-type (WT) and transgenic APPSWE/PS1∆E9 murine models of AD (AD+) across an array of irradiance, chromaticity, and contrast conditions. Substantial color and contrast-mode alternation deficits appear in AD+ mice at an age when hippocampal-based memory and learning is still intact. Profiling of timespan, entries and transition patterns between the different arms uncovers variable AD-associated impairments in contrast sensitivity and color discrimination, reminiscent of tritanomalous defects documented in AD patients. Transition deficits are found in aged WT mice in the absence of alternation decline. Overall, ViS4M is a versatile, controlled device to measure color and contrast-related vision in aged and diseased mice.

Download Full-text

Synaptic Loss in Alzheimer's Disease: Mechanistic Insights Provided by Two-Photon in vivo Imaging of Transgenic Mouse Models

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2020.592607 ◽

2020 ◽

Vol 14 ◽

Author(s):

Jaichandar Subramanian ◽

Julie C. Savage ◽

Marie-Ève Tremblay

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Models ◽

Synaptic Loss ◽

Two Photon ◽

Synapse Loss ◽

Disease Mutations ◽

The Brain

Synapse loss is the strongest correlate for cognitive decline in Alzheimer's disease. The mechanisms underlying synapse loss have been extensively investigated using mouse models expressing genes with human familial Alzheimer's disease mutations. In this review, we summarize how multiphoton in vivo imaging has improved our understanding of synapse loss mechanisms associated with excessive amyloid in the living animal brain. We also discuss evidence obtained from these imaging studies for the role of cell-intrinsic calcium dyshomeostasis and cell-extrinsic activities of microglia, which are the immune cells of the brain, in mediating synapse loss.

Download Full-text