Amyloid aggravates tauopathy: stronger deficits in hippocampal and prefrontal neuroplasticity and fear memory in APP.V717IxTau.P301L vs. Tau.P301L mice
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1
Katholieke Universiteit Leuven, Brain and Cognition, Belgium
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2
Qatar Biomedical Research Institute, Neurological Disorder Research Center, Qatar
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3
KU Leuven, Department of Human Genetics, Belgium
Alzheimer’s disease is a neurodegenerative disorder characterized by memory deficits and executive dysfunctions in the early stages of the disease. The two major pathological hallmarks of AD are extracellular amyloid plaques and intracellular neurofibrillary tangles (NFTs). Hyperphosphorylation of Tau and especially synaptic loss in prefrontal cortex (PFC) and hippocampus (HC) appear as the best patho-morphological correlates of cognitive and functional deficits observed in AD. Interestingly, it has been suggested that amyloid may favour tau phosphorylation by activation of several kinases/phosphatases. Accordingly, it is hypothesized that amyloid exacerbates tau-pathology (Terwel et al., 2008). Both cognitive decline and psychiatric symptoms are caused by dysfunctions of synaptic processes. Consequently, it is tempting to use measures of synaptic function as sensitive readouts for the underlying disease mechanisms. Moreover, perturbed anxiety-related memories and impaired high order cognition are found in early stages of AD.
We employed mice overexpressing mutant human Tau.P301L and APP.V717I x Tau.P301L (biAT) (Terwel et al., 2008), backcrossed into C57BL/6J background. Tau.P301L mice reflect tauopathy, while their bigenic littermates display a progressive combination of amyloid- and tau-pathology. We performed fEPSP recordings in acute brain slices from 3-5 month-old animals, either by conventional glass micro-electrodes in prefrontal cortex or via multi-electrode arrays in hippocampal slices. Contextual fear memory and seven days of extinction learning were evaluated at the same age in a different cohort.
Both models showed impaired LTP in prefrontal cortex and hippocampal CA1. In contrast, LTP levels in dentate gyrus were normal, despite reduced basal transmission. We further observed altered paired-pulse responses and more epileptiform activity in CA1. biAT and Tau animals had increased freezing in the new context (pre-CS) with biAT tending to freeze more than Tau, which suggests enhanced general fear response compared to WT. This is indicative of increased anxiety and/or an overgeneralization of the learned fear response to a somewhat similar context. During the extinction period, the biAT displayed significantly more freezing than Tau and even more than WT during the first 3 days, supporting impaired extinction of previous contextual memory association.
The impaired LTP in PFC and CA1 of young Tau.P301L and biAT mice points towards prodromal synaptic dysfunctions in these regions. These findings coincide with inappropriate anxiety responses in situations that were similar to remembered harmful situations (i.e., excessive memory generalization). Interestingly, biAT mice seem to perform generally worse than Tau mice, providing further support for the hypothesis that amyloid aggravates tau pathology.
Acknowledgements
This work was supported by research grants from the Fonds voor Wetenschappelijk Onderzoek Vlaanderen (G058714 and G0D76114) and an interdisciplinary research grant from KU Leuven (GOA 12/008). The authors are indebted to reMYND (Heverlee, Belgium) for providing the C57*Bl6 APPxTau mice.
References
Terwel D., Muyllaert D., Dewachter I., Borghgraef P., Croes S., Devijver H. and Van Leuven F. (2008). Amyloid Activates GSK-3beta to Aggravate Neuronal Tauopathy in Bigenic Mice. Am. J. Pathol. 172 (3):786-798. http://dx.doi.org/10.2353/ajpath.2008.070904
Keywords:
tau pathology,
synaptic plasticity,
Prefrontal Cortex,
Hippocampus,
fear memory,
Amyloid beta
Conference:
12th National Congress of the Belgian Society for Neuroscience, Gent, Belgium, 22 May - 22 May, 2017.
Presentation Type:
Oral Presentation
Topic:
Disorders of the Nervous System
Citation:
Latif-Hernandez
A,
Schreurs
A,
Ahmed
T,
Van Leuven
F,
D'Hooge
R and
Balschun
D
(2019). Amyloid aggravates tauopathy: stronger deficits in hippocampal and prefrontal neuroplasticity and fear memory in APP.V717IxTau.P301L vs. Tau.P301L mice.
Front. Neurosci.
Conference Abstract:
12th National Congress of the Belgian Society for Neuroscience.
doi: 10.3389/conf.fnins.2017.94.00043
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Received:
25 Apr 2017;
Published Online:
25 Jan 2019.
*
Correspondence:
Ms. Amira Latif-Hernandez, Katholieke Universiteit Leuven, Brain and Cognition, Leuven, Belgium, amira.latifhernandez@ppw.kuleuven.be