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 1

Mutated APP overexpression impairs long-term but not short-term synaptic plasticity and memory in Mapt-KO mice.

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Mutated APP overexpression impairs long-term but not short-term synaptic...
(A) Basal neurotransmission is normal in Mapt-KO and TgAPP slices (ANOVA for repeated measures F(2,26) = 1.639, P = 0.108), but impaired in TgAPP/Mapt-KO slices (ANOVA for repeated measures F(1,17) = 31.106, P < 0.0001; n = 9 WT, n = 9 TgAPP, n = 12 Mapt-KO, n = 11 TgAPP/Mapt-KO). (B) Endogenous tau suppression does not protect TgAPP slices against LTP impairment (ANOVA for repeated measures F(1,18) = 6.085, P = 0.01, WT vs. TgAPP; ANOVA for repeated measures F(1,21) = 5.119, P < 0.05, WT vs. TgAPP/Mapt-KO; n = 11 WT, n = 9 TgAPP, n = 12 Mapt-KO, n = 11 TgAPP/Mapt-KO). (C) Analysis of slices displayed in B shows normal LTP at 30 minutes after tetanus in TgAPP/Mapt-KO slices (1-way ANOVA with Bonferroni correction P = 1, WT vs. TgAPP/Mapt-KO), but not at 120 minutes (P < 0.05). (D) RAWM performance is impaired in TgAPP and TgAPP/Mapt-KO mice (ANOVA for repeated measures, day 2 F(3,39) = 5.961, P = 0.002; 1-way ANOVA with Bonferroni correction P < 0.05 in WT vs. TgAPP and P = 0.005 vs. TgAPP/Mapt-KO for block 8; n = 10 WT, n = 11 TgAPP, n = 10 Mapt-KO, n = 12 TgAPP/Mapt-KO). (E) Contextual fear memory is impaired in TgAPP and TgAPP/Mapt-KO mice at 24 hours after training (1-way ANOVA, F(3,35) = 8.897, P < 0.0001; Bonferroni’s P < 0.005, WT vs. TgAPP; P < 0.05, WT vs. TgAPP/Mapt-KO mice; n = 10 WT, n = 9 TgAPP, n = 10 Mapt-KO, n = 10 TgAPP/Mapt-KO). (F) Endogenous tau suppression protects TgAPP mice against short-term contextual fear memory impairment (1-way ANOVA with Bonferroni correction P = 0.472, WT vs. TgAPP/Mapt-KO mice; n = 11 WT, n = 13 TgAPP, n = 10 Mapt-KO, n = 13 TgAPP/Mapt-KO). (G) Cued fear memory is impaired in TgAPP and TgAPP/Mapt-KO mice (1-way ANOVA with Bonferroni correction F(3,35) = 10.207, P < 0.0001; Bonferroni’s P < 0.01 for both genotypes vs. WT). (H) Endogenous tau suppression does not influence amyloid load in TgAPP mice (2-sample unpaired t test, t(6) = 0.766 P > 0.05; n = 4 for both groups). *P < 0.05; **P < 0.01; §P < 0.0001.