Amylin Administration Exacerbates Tauopathy by Impairing Lysosomal Mechanisms in a Hybrid Diabetes Model
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Amylin Administration Exacerbates Tauopathy by Impairing Lysosomal Mechanisms in a Hybrid Diabetes Model

01/07/2025 Compuscript Ltd
Amylin, a peptide hormone known for its aggregation in the pancreas during type-2 diabetes, may trigger several Alzheimer's disease (AD)-related pathological mechanisms, including neuroinflammation and cognitive deficits. Although it has been reported that amylin can affect tau pathology in an AD mouse model, the cellular mechanisms underlying the interaction between tau and amylin remain poorly understood.

This research, published in the Genes & Diseases journal by a team from University of South Florida, analyzed the interaction between amylin and tau pathology to uncover how diabetes can influence the risk of developing AD.

Initially, the researchers administered streptozotocin (STZ) and/or amylin peripherally to the PS19 model of tauopathy at 3 months and evaluated the mice at 6 months of age. The team found that STZ reduced body weight gain, increased blood glucose levels, impaired motor performance, and improved fear-conditioned memory in PS19 mice, hallmarks often associated with neurodegenerative progression.

Remarkably, both amylin and STZ administration not only induced the emergence of tau pathology in the pancreas, but also led to a decline in the number of lysosomes in pancreatic islets. Interestingly, mice treated with amylin and STZ also developed robust tau pathology associated with lowering lysosomal cathepsin D (CatD) levels in the visual cortex, indicating impaired protein clearance mechanisms. Surprisingly, the pancreas also exhibited tau pathology in diabetic mice, especially in those receiving both STZ and amylin, alongside reduced lysosomal markers such as LAMP1 in islet cells. This finding underscores the intricate and bidirectional relationship between diabetes and AD.

In summary, this study demonstrates that amylin, in synergy with diabetes, exacerbates tau pathology by impairing lysosomal activity in the visual cortex. Overall, the findings of this research enhance our understanding of the cellular pathways through which amylin may serve as a link in the pancreas-brain axis during diabetes, influencing the risk of developing tau pathology.

Reference

Title of Original Paper: Amylin exacerbates tau pathology in the visual cortex of diabetic mice by impairing lysosomal activity

Journal: Genes & Diseases

Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch

DOI: https://doi.org/10.1016/j.gendis.2025.101602

Funding Information:
US National Institutes on Aging (No. AG057290)

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

Scopus CiteScore: 8.4 | Impact Factor: 9.4

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eISSN: 2352-3042
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Attached files
  • (A–D) After the end of treatments, PS19 mice did not present differences in the working memory (Y-maze test) (A) (CIT/PBS, n = 11; STZ/PBS, n = 14; CIT/AMY, n = 10; CIT/AMY, n = 12), recognition memory in novel object recognition test (NOR) (B) (CIT/PBS, n = 11; STZ/PBS, n = 14; CIT/AMY, n = 9; CIT/AMY, n = 14), and spatial memory in the Morris water maze test (MWM) (C, D) (CIT/PBS, n = 10; STZ/PBS, n = 14; CIT/AMY, n = 9; CIT/AMY, n = 13). (E, F) STZ/PBS and STZ/AMY had a better performance in the contextual fear conditioning test (CFC) in comparison with CIT/PBS and CIT/AMY in the training and test sessions (P < 0.05; CIT/PBS, n = 10; STZ/PBS, n = 14; CIT/AMY, n = 9; CIT/AMY, n = 13).
  • (A) Schematic representation of a sagittal mouse brain section from the Allen Brain Atlas. PS19 mice sections were stained with mAb AT8 (left panel) or mAb MC1 (right panel). (B) AT8 staining was quantified in the prefrontal cortex (PFC), hippocampus (H), and visual cortex (V. Cx). (B, E) STZ/AMY mice presented a larger AT8 and MC1+ stained area in the visual cortex in comparison with CIT/PBS and CIT/AMY (P < 0.05; n = 6 for all groups). (C, D) No differences were detected in the PFC (C), hippocampus (D), and other areas, such as the entorhinal cortex and amygdala.
  • The intraperitoneal administration of amylin aggregates caused the emergence of pathogenic p-tau concomitant with a decrease in lysosomes in the pancreas of diabetic PS19 mice. Although the plasmatic amylin remained unchanged in mice at 6 months of age, we speculate that a fraction of amylin aggregates may have reached the brain during the two-week injection period (4.5 months). Peripheral amylin aggregates, through a yet unknown mechanism, contributed to the exacerbation of p-tau in the visual cortex. The increase of p-tau in the visual cortex was accompanied by decreased lysosome functionality. However, the chronological order of these events still needs to be clarified. Further research is necessary to fully understand the spatial and temporal order and the mechanisms underlying the involvement of amylin in the aggregation of tau in both the central nervous system and the periphery.
01/07/2025 Compuscript Ltd
Regions: Europe, Ireland
Keywords: Health, Medical, Science, Life Sciences

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