Journal Article

FZJ-2023-02431

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Reversal of Tau-Dependent Cognitive Decay by Blocking Adenosine A1 Receptors: Comparison of Transgenic Mouse Models with Different Levels of Tauopathy

Anglada-Huguet, M. ; Endepols, H.FZJ* ; Sydow, A. ; Hilgers, R. ; Neumaier, B.FZJ* ; Drzezga, A.FZJ* ; Kaniyappan, S. ; Mandelkow, E. ; Mandelkow, E.-M. (Corresponding author)

2023
Molecular Diversity Preservation International Basel

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Please use a persistent id in citations: http://hdl.handle.net/2128/34585  doi:10.3390/ijms24119260

Abstract: The accumulation of tau is a hallmark of several neurodegenerative diseases and is associatedwith neuronal hypoactivity and presynaptic dysfunction. Oral administration of the adenosineA1 receptor antagonist rolofylline (KW-3902) has previously been shown to reverse spatial memorydeficits and to normalize the basic synaptic transmission in a mouse line expressing full-lengthpro-aggregant tau (TauDK) at low levels, with late onset of disease. However, the efficacy of treatmentremained to be explored for cases of more aggressive tauopathy. Using a combination of behavioralassays, imaging with several PET-tracers, and analysis of brain tissue, we compared the curativereversal of tau pathology by blocking adenosine A1 receptors in three mouse models expressingdifferent types and levels of tau and tau mutants. We show through positron emission tomographyusing the tracer [18F]CPFPX (a selective A1 receptor ligand) that intravenous injection of rolofyllineeffectively blocks A1 receptors in the brain. Moreover, when administered to TauDK mice, rolofyllinecan reverse tau pathology and synaptic decay. The beneficial effects are also observed in a line withmore aggressive tau pathology, expressing the amyloidogenic repeat domain of tau (TauRDDK) withhigher aggregation propensity. Both models develop a progressive tau pathology with missorting,phosphorylation, accumulation of tau, loss of synapses, and cognitive decline. TauRDDK causespronounced neurofibrillary tangle assembly concomitant with neuronal death, whereas TauDK accumulatesonly to tau pretangles without overt neuronal loss. A third model tested, the rTg4510line, has a high expression of mutant TauP301L and hence a very aggressive phenotype starting at~3 months of age. This line failed to reverse pathology upon rolofylline treatment, consistent with ahigher accumulation of tau-specific PET tracers and inflammation. In conclusion, blocking adenosineA1 receptors by rolofylline can reverse pathology if the pathological potential of tau remains below athreshold value that depends on concentration and aggregation propensity.

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Contributing Institute(s):

1. Nuklearchemie (INM-5)
2. Molekulare Organisation des Gehirns (INM-2)

Research Program(s):

1. 5253 - Neuroimaging (POF4-525) (POF4-525)
2. 5252 - Brain Dysfunction and Plasticity (POF4-525) (POF4-525)

Appears in the scientific report 2023

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