Tau reduction prevents Abeta-induced defects in axonal transport

Abstract

Amyloid-β (Aβ) peptides, derived from the amyloid precursor protein, and the microtubule-associated protein tau are key pathogenic factors in Alzheimer's disease (AD). How exactly they impair cognitive functions is unknown. We assessed the effects of Aβ and tau on axonal transport of mitochondria and the neurotrophin receptor TrkA, cargoes that are critical for neuronal function and survival and whose distributions are altered in AD. Aβ oligomers rapidly inhibited axonal transport of these cargoes in wild-type neurons. Lowering tau levels prevented these defects without affecting baseline axonal transport. Thus, Aβ requires tau to impair axonal transport, and tau reduction protects against Aβ-induced axonal transport defects.

Figure 1

(A) Anterograde axonal movement of a single mitochondrion (yellow triangles) is shown in successive 5-s image frames. (B) The microtubule-depolymerizing agent nocodazole (10 µg/ml) and oligomeric Aβ_1-42 (2 µM) inhibited mitochondrial movements in Tau^+/+ axons within 60 min. Aβ with a scrambled amino acid sequence (Aβ_{1-42-Scrambled}, 2 µM) had no effect. n = 7–24 axons per condition. **P<0.01, ***P<0.001 versus corresponding baseline (paired t tests with Bonferroni correction). (C) Aβ_1-42 inhibited mitochondrial movements in Tau^+/+ axons within 20 min. n = 7–8 axons for each data point. **P<0.01 versus corresponding baseline (paired t tests, Bonferroni). (D–F) Aβ_1-42 inhibited mitochondrial (D, E) and TrkA (F) motility in Tau^+/+ axons within 60 min but not in Tau^+/− or Tau^−/− axons. n = 24–45 axons for each genotype and condition. **P<0.01, ***P<0.001 versus corresponding baseline (paired t tests, Bonferroni). The percent reduction in anterograde transport in the presence of Aβ was greater in Tau^+/+ axons than in Tau^+/− or Tau^−/− axons (D, F). ^#P<0.05, ^##P<0.01 (Kruskal-Wallis ANOVA, Dunn). Error bars are SEM. See also Table S1.