Tau is not necessary for amyloid-β–induced synaptic and memory impairments
Daniela Puzzo, … , Paul E. Fraser, Ottavio Arancio
Daniela Puzzo, … , Paul E. Fraser, Ottavio Arancio
Published June 16, 2020
Citation Information: J Clin Invest. 2020;130(9):4831-4844. https://doi.org/10.1172/JCI137040.
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Research Article Neuroscience

Tau is not necessary for amyloid-β–induced synaptic and memory impairments

Abstract

The amyloid hypothesis posits that the amyloid-beta (Aβ) protein precedes and requires microtubule-associated protein tau in a sort of trigger-bullet mechanism leading to Alzheimer’s disease (AD) pathology. This sequence of events has become dogmatic in the AD field and is used to explain clinical trial failures due to a late start of the intervention when Aβ already activated tau. Here, using a multidisciplinary approach combining molecular biological, biochemical, histopathological, electrophysiological, and behavioral methods, we demonstrated that tau suppression did not protect against Aβ-induced damage of long-term synaptic plasticity and memory, or from amyloid deposition. Tau suppression could even unravel a defect in basal synaptic transmission in a mouse model of amyloid deposition. Similarly, tau suppression did not protect against exogenous oligomeric tau–induced impairment of long-term synaptic plasticity and memory. The protective effect of tau suppression was, in turn, confined to short-term plasticity and memory. Taken together, our data suggest that therapies downstream of Aβ and tau together are more suitable to combat AD than therapies against one or the other alone.

Authors

Daniela Puzzo, Elentina K. Argyrousi, Agnieszka Staniszewski, Hong Zhang, Elisa Calcagno, Elisa Zuccarello, Erica Acquarone, Mauro Fa’, Domenica D. Li Puma, Claudio Grassi, Luciano D’Adamio, Nicholas M. Kanaan, Paul E. Fraser, Ottavio Arancio

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Figure 5

Reconstitution of Tau expression reestablishes oAβ-induced disruption of short-term synaptic plasticity and memory.

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Reconstitution of Tau expression reestablishes oAβ-induced disruption of...
(A) Similar levels of human and murine tau expression in htau/Mapt-KO and WT mice. (B) Tau monomer (1.3–10 nM) standard curve (r2 = 0.92) used to interpolate total tau and tau aggregate (0.16–1.3 nM) standard curve (r2 = 0.99) used to interpolate oTau. Assessment of total tau in hippocampus/cortex of 8- and 17-month-old htau/Mapt-KO mice (2-sample t test, t(6) = 17.983, P < 0.0001 compared with Mapt-KO at 8 months, n = 4/4; t(8) = 19.379 compared with 17 months, n = 5/5), and oTau levels (2-sample t test, t(6) = 12.044, P < 0.0001 compared with Mapt-KO at 8 months, n = 4/4; t(8) = 21.354 compared with 17 months, n = 5/5). Note the lack of signal in tau monomer standard curve in oTau assays demonstrating the specificity for oligomeric species. (C) Basal neurotransmission is similar in WT, Mapt-KO and htau/Mapt-KO slices (ANOVA for repeated measures F(2,40) = 3.865, P = 0.639; n = 15/11/17, respectively). (D) Subtoxic extracellular oAβ (50 nM) impairs LTP in htau/Mapt-KO slices (ANOVA for repeated measures F(1,15) = 33.474, P < 0.0001 vs. WT+vehicle; n = 8 WT+vehicle, n = 8 WT+oAβ, n = 7 Mapt-KO+vehicle, n = 8 Mapt-KO+oAβ, n = 7 htau/Mapt-KO+vehicle, n = 9 htau/Mapt-KO+oAβ). (E) Analysis of slices displayed in D shows LTP impairment at 120 and 30 minutes after tetanus (1-way ANOVA with Bonferroni correction P < 0.05 vs. WT or htau/Mapt-KO+vehicle). (F) Subtoxic oAβ (75 nM) impairs RAWM performance in htau/Mapt-KO mice (day 2 ANOVA for repeated measures F(5,73) = 3.412, P = 0.008; 1-way ANOVA with Bonferroni correction P < 0.05 vs. WT+vehicle; P < 0.005 vs. htau/Mapt-KO+vehicle, block 10; n = 13 WT+vehicle, n = 13 WT+oAβ, n = 12 Mapt-KO+vehicle, n = 14 Mapt-KO+oAβ, n = 14 htau/Mapt-KO+vehicle, n = 14 htau/Mapt-KO+oAβ). (G and H) oAβ 75 nM impairs contextual fear memory in htau/Mapt-KO mice at 24 hours (1-way ANOVA with Bonferroni correction F(5,86) = 3.504, P < 0.01, Bonferroni’s P < 0.05; n = 13 WT+vehicle, n = 16 WT+oAβ, n = 18 Mapt-KO+vehicle, n = 9 Mapt-KO+oAβ, n = 19 htau/Mapt-KO+vehicle, n = 18 htau/Mapt-KO+oAβ) and 30 minutes after training (1-way ANOVA with Bonferroni correction F(5,62) = 3.897, P < 0.005; Bonferroni’s P < 0.05, n = 11 WT+vehicle, n = 10 WT+oAβ, n = 12 Mapt-KO+vehicle, n = 10 Mapt-KO+oAβ, n = 12 htau/Mapt-KO+vehicle, n = 13 htau/Mapt-KO+oAβ). (I) Cued fear memory is similar in the 6 groups of mice displayed in G (1-way ANOVA F(5,79) = 1.481, P = 0.205). *P < 0.05; **P < 0.01; ***P < 0.005.