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Synaptic stimulation protects against pathologic tau

Models of Alzheimer’s disease cast new light on the therapeutic potential of synaptic stimulation, which seems to involve enhanced lysosomal degradation of tau oligomers. AAIC2020 also heard evidence that extracellular vesicles seed tau spread and can provide valuable insights into altered mitochondrial and metabolic function in tauopathies.

Synaptic stimulation protects against tau pathology in transgenic mouse models of Alzheimer’s disease and restores synaptic proteins to levels seen in wild-type animals,1 Davide Tampellini (Inserm, Université Paris Sud, France) told AAIC2020. This work may cast light on mechanisms underlying the potential clinical benefits of deep brain stimulation (DBS),2 and the protective effects of participation in intellectually challenging activity,3 he suggested.

In the studies described by Professor Tampellini, synaptic stimulation via DBS electrodes chronically implanted in the entorhinal cortex of transgenic mice reduced hippocampal levels of tau oligomers and hyperphosphorylated tau and increased levels of synaptophysin.1

Increasing synapse activity reduces tau pathology. Inhibiting synaptic activity does the opposite

The reverse was also true: chronic inhibition of synaptic activity in PS19 mice – achieved by the removal of whisker follicles from one side of the animals’ snouts -- resulted in the build-up of tau oligomers and hyperphosphorylated tau and reduced levels of synaptophysin. 

 

Protection requires lysosomal activity

Professor Tampellini and colleagues have also shown that reduced accumulation of pathological forms of tau and enhanced synaptic function can be caused by chemically-induced synaptic stimulation.

It seems that synaptic activation promotes clearance of tau oligomers by autophagosomes and lysosomes rather than via the proteasomal system. Activation reduced pathological tau and lysosomal size and increased lysosomal degradation. Inhibition of activity led to tau accumulation within swollen lysosomes.

Ongoing studies of cultured neurons point to a role for Transcription Factor (TF)EB in promoting lysosomal degradation following synaptic stimulation.

Rationale for the therapeutic use of deep brain stimulation

Earlier work by the same group had shown that stimulation of synaptic activity is also protective in transgenic mouse models of β-amyloidosis.4

 

Other threads in the tau tangle

In the words of Stephanie Fowler (University College, London, UK), extracellular vesicles (EVs) are purpose-made to transfer cargos from cell to cell. Work she presented on post mortem tissue showed that EVs from people who had AD, but not EVs from healthy controls, are rich in small C-terminal tau fragments. Moreover, these fragments are capable of seeding tau aggregation in rat neurons.

Extracellular vesicles contain seed-competent tau species

EVs are a mirror into the whole brain, Dr Fowler continued, and provide proteomic clues to the identity of the cell populations that are selectively vulnerable in human tauopathies.

Along with altered synaptic activity, reduced brain metabolism is an early sign of AD. AAIC2020 also heard fresh insights into the importance of the mammalian target of rapamycin complex 1 (mTORC1) in the dysfunctional nutrient sensing and protein synthesis seen in diseases of aging.

Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.

References

1. Akwa Y, et al. Mol Psychiatry 2018; 23:1530-40

2. McKinnon C, et al. Ann Clin Transl Neurol 2018;6:174-185

3. Stern Y. Alzheimer Dis Assoc Disord 2006;20:112-7

4. Tampellini D et al. J Neurosci 2010;30:14299-304

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