Age-dependent changes in synaptic plasticity enhance tau oligomerization in the mouse hippocampus

Abstract

The aggregation mechanism of phosphorylated tau is an important therapeutic target for tauopathies, including Alzheimer’s disease, although the mechanism by which aggregation occurs is still unknown. Because the phosphorylation process of tau is involved in the trafficking of AMPA receptors, which accompanies the long-term depression (LTD) of synapses, we examined the effect of LTD-inducing low-frequency stimulation (LFS) on the formation of pathological tau aggregates in adult and aged wild-type mice. Our biochemical analysis demonstrated that LFS led to the formation of sarkosyl-insoluble (SI) tau oligomers in aged hippocampi but not in adult hippocampi in wild-type mice. In parallel, electrophysiological experiments showed an increased contribution of the autophagy-lysosomal pathway (ALP) to LTD during aging, although the other properties of LFS-induced LTD that we investigated were not altered. Thus, we anticipate that the increased contribution of the ALP to the LTD cascade is involved in the age-dependent formation of tau oligomers that results from LFS. Analysis of the LC3 ratio, an indicator of autophagosome formation, showed that LFS increased cleaved LC3 (type II) in the aged hippocampus relative to type I LC3, suggesting potentiation of the ALP accompanied by LTD. Pharmacological inhibition of autophagosome formation depressed LFS-induced oligomerization of tau. Prevention of lysosomal function in the ALP enhanced the formation of tau oligomers by LFS. These results suggest the importance of the autophagosome for the LFS-induced oligomerization of tau and suggest a reason for its age dependency. Interestingly, the lysosomal disturbance promoted the formation of the fibrillar form of aggregates consisting of hyper-phosphorylated tau. The LTD-ALP cascade potentially acts as one of the suppliers of pathological aggregates of tau in aged neurons.Electronic supplementary materialThe online version of this article (10.1186/s40478-017-0469-x) contains supplementary material, which is available to authorized users.

Changes in Metabolism and Proteostasis Drive Aging Phenotype in Aplysia californica Sensory Neurons

“…Disruptions of synaptic plasticity as a result of impaired signaling drive cognitive declines typical of brain aging ( Magnusson et al, 2010 ; Haxaire et al, 2012 ; Morrison and Baxter, 2012 ). While these neuronal signatures are known to occur even in non-pathological aging, they are also typical of major neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease ( Silvestri and Camaschella, 2008 ; Thomsen et al, 2015 ; Foster et al, 2017 ; Grimm and Eckert, 2017 ; Kimura et al, 2017 ).…”

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“… The interplay between autophagy and synaptic activity. In the normal cell, autophagy is both modulated by [ 90, 94, 101, 105, 107, 110, 111 ] and modulates [ 79, 86, 89, 91 ] synaptic activity to fine-tune synaptic function. Theoretically, autophagic activity can therefore be up or down regulated to either increase or decrease the amount of synaptic protein turnover.…”

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