# Amylin exacerbates tau pathology in the visual cortex of diabetic mice by impairing lysosomal activity

## TL;DR

This study shows that amylin, a peptide linked to diabetes, worsens tau-related brain damage in diabetic mice by disrupting lysosomal function in the visual cortex.

## Contribution

The study reveals a novel mechanism by which amylin in diabetes exacerbates tau pathology through lysosomal dysfunction in the brain.

## Key findings

- Amylin and streptozotocin reduced pancreatic lysosomes and increased tau pathology in diabetic mice.
- Amylin administration worsened tau pathology in the visual cortex alongside reduced cathepsin D levels.
- Lysosomal impairment in the brain may link pancreatic amylin aggregation to neurodegeneration.

## Abstract

The aggregation of the peptide hormone amylin in the pancreas is a pathological hallmark of type-2 diabetes. Additionally, amylin can form aggregates in the brain, promoting β-amyloid deposition and tau phosphorylation in Alzheimer's disease. The cross-seeding between amylin and tau exacerbates tau pathology spread and synaptic loss, leading to neurodegeneration and cognitive deficits. Given the link between lysosomal dysfunction and tauopathy in the brain and amylin aggregation in the pancreas, we hypothesized that amylin could potentially worsen tau pathology in diabetic mice. We administered streptozotocin and/or amylin peripherally to the PS19 model of tauopathy at 3 months and characterized them at 6 months of age. We found that streptozotocin diminished body weight gain, increased blood glucose levels, worsened motor performance, and improved fear-conditioned memory in PS19 mice. Both amylin and streptozotocin administration prompted the emergence of tau pathology in the pancreas, which coincided with a decrease in the number of lysosomes in pancreatic islets. Mice treated with amylin and streptozotocin also developed robust tau pathology concomitant with lowering lysosomal cathepsin D levels in the visual cortex. These findings suggest that in diabetic mice, amylin administration diminished pancreatic lysosomes, possibly increasing the number of amylin aggregates that reached the brain and contributing to the worsening of tau pathology due to lysosomal impairment in the visual cortex. The outcome of our research enhances the understanding of the cellular pathways by which amylin may serve as a link between the pancreas-brain axis during diabetes, influencing the risk of developing tau pathology.