Editors' ChoiceDiabetes

Insulin: To the periphery and beyond

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Science Translational Medicine  03 May 2017:
Vol. 9, Issue 388, eaan3776
DOI: 10.1126/scitranslmed.aan3776


Increased tau phosphorylation resulting from insulin depletion is reversed by insulin treatment in a murine model.

Diabetes is an established risk factor for Alzheimer’s Disease (AD), spurring research into the roles of both insulin depletion and insulin resistance in AD. Although insulin is best known to regulate peripheral glucose, it can also traverse the blood-brain barrier, and interventions thought to improve insulin signaling are being investigated in AD clinical trials. However, the relationship between diabetes and brain neuropathology is both complex and controversial, and the underlying mechanisms mediating such a relationship are unclear.

In the current study, van der Harg et al. first established that insulin depletion using the streptozotocin (STZ) rodent model increased tau phosphorylation. In humans, tau phosphorylation tracks with cognitive decline, and the degree of subsequent neurofibrillary tangle formation is an important post-mortem marker of AD severity. Here, cortical tau phosphorylation was increased just 5 days after STZ treatment and was followed by hippocampal tau phosphorylation. The activity and expression of most phosphatases and kinases involved in tau regulation were unchanged, with the exception of striking increases in protein kinase A (PKA) activity and expression. PKA activity in post-mortem brains from AD patients and elderly controls revealed similar changes that were related to disease stage. PKA activity was higher in patients with earlier stage AD (Braak Stage 4) compared with controls or AD patients with most severe tangle pathology (Braak Stage 6), suggesting a role for PKA earlier in the neurodegenerative process. Most intriguingly, authors repeated the STZ depletion study and intervened in the time frame when the increase in phosphorylated tau was evident. Treatment with a slow-release insulin pellet increased insulin concentration without affecting plasma glucose. In insulin-treated animals, the insulin depletion-related increases in both phosphorylated tau and active PKA were ameliorated.

The findings from these experiments show that increases in PKA activity are evident in earlier, rather than later, stages of neurofibrillary tangle pathology in human AD brain. The study also indicates that insulin depletion–related increases in PKA activity and tau phosphorylation return to normal in animals receiving insulin treatment. More broadly, this suggests that tau phosphorylation may be preventable and that early-stage accumulations of cerebral pathological tau may be reversed.

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