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Mouse Footpad Inoculation Model to Study Viral-Induced Neuroinflammatory Responses
Published on: June 14, 2020
Basic Science and Pathogenesis
Jamie L Fournier1,2,3, Aya Arrar1,2,3, Madison R Longmuir1,2,3
1University of Western Ontario, London, ON, Canada.
Background:
Tau is a microtubule stabilizing protein that becomes dysfunctional during the course of Alzheimer's Disease. Previous research has shown that individually amyloid and APOE4 have the potential to increase tau phosphorylation and worsen tau pathology in tau mutant models of tauopathy. However, whether both amyloid and APOE4 can further contribute to tau dysfunction in mouse models that more faithfully reflect the levels of tau in humans is unknown. We developed mouse models with a combination of incorporated humanized knock-in variants of hMAPT, AppNL and AppNL-F and APOE 3 or APOE 4 genotypes.
Method:
Biochemical and imaging techniques including immunofluorescence microscopy and Western Blots were performed for phosphorylated tau at the Serine 202/Threonine 205 sites (AT8) and total tau. Visuospatial learning and memory were assessed using the Paired Associates Learning (PAL) task, an automated touchscreen task.
Result:
Our preliminary results indicated that tau protein phosphorylated at the Serine 202/Threonine 205 phosphorylation site is detected in in both male and female mice in a genotype dependent manner. Aging, expression of App NL-F and APOE4 increased tau phosphorylation. Insoluble total tau was found predominantly in aged mice (18 months) and was worse in APOE4 expressing individuals. All the antibodies used detected no signal in tissue from tau knockout mice confirming the results are a consequence of changes in tau. Preliminary results indicate that 12-month old App NL and App NL-F mice (ApoE3 and ApoE4) were able to learn the PAL task to 70% accuracy. There were no genotype-dependent differences in performance.
Conclusion:
The results of this project demonstrate that tau pathology markers appear to increase as a function of age, APOE4 and the ability to accumulate insoluble Abeta and plaques. These results agree with the notion that amyloid and APOE4 can increase tau markers even in less aggressive animal models without tau overexpression or mutations. Our findings also suggest that there are no genotype-dependent differences in learning and memory in the PAL task at early ages, despite these mice presenting other cognitive deficits at that stage.
Insights
Alzheimer's Disease research shows amyloid and APOE4 worsen tau pathology. New mouse models reveal aging, amyloid precursor protein (App), and APOE4 increase tau phosphorylation and insoluble tau, especially in APOE4 carriers.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Tau protein dysfunction is central to Alzheimer's Disease (AD).
- Amyloid-beta (Aβ) and Apolipoprotein E4 (APOE4) individually exacerbate tau pathology.
- The combined effects of Aβ and APOE4 on human tau levels in vivo remain unclear.
Purpose of the Study:
- To investigate the synergistic effects of Aβ and APOE4 on human tau pathology.
- To utilize novel mouse models expressing humanized variants of tau (hMAPT), amyloid precursor protein (AppNL/NL-F), and APOE3/APOE4.
Main Methods:
- Biochemical assays (Western Blot) and immunofluorescence microscopy were used to quantify phosphorylated tau (AT8) and total tau.
- Visuospatial learning and memory were assessed using the Paired Associates Learning (PAL) task.
Main Results:
- Tau phosphorylation (AT8) increased with age, AppNL-F expression, and APOE4 genotype.
- Insoluble total tau was elevated in aged mice and exacerbated by APOE4.
- No significant genotype-dependent differences in learning and memory were observed in the PAL task at 12 months.
Conclusions:
- Aging, APOE4, and Aβ accumulation correlate with increased tau pathology markers.
- Amyloid and APOE4 can enhance tau markers in models without tau overexpression.
- Early-stage cognitive deficits may exist despite normal performance on the PAL task.
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