GM‐CSF reduces amylin amyloid, inhibits pancreatic apoptosis, and sustains lowered blood glucose levels in the hIAPP mouse model of Type 2 diabetes mellitus, a known risk factor for Alzheimer’s disease

• Published in: Alzheimer's & dementia Vol. 19; no. S13
• Main Authors: Wang, Athena Ching‐Jung, Boyd, Timothy D., Adame, Vanesa, Potter, Huntington
• Format: Journal Article
• Language: English
• Published: 01.12.2023
• ISSN: 1552-5260; 1552-5279
• DOI: 10.1002/alz.080349

Background People with Type II diabetes mellitus (T2D) are at higher risk for developing Alzheimer’s disease (AD). T2D is characterized histopathologically by accumulation of pancreatic amyloid deposits comprised primarily of self‐aggregating amylin/human islet amyloid polypeptide (hIAPP). Amylin is implicated in both T2D and AD pathogenesis, and in T2D patients, pancreatic amyloid deposition occurs before and induces islet β‐cell apoptosis. Granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) has demonstrated anti‐apoptotic, neuroprotective, neurotrophic, immunomodulatory, and regenerative effects in several neuronal injury models. We discovered that GM‐CSF treatment rapidly reduced cerebral amyloidosis and reversed cognitive impairment in transgenic AD models (Boyd et al, 2010), which led to the initiation and successful completion of a Phase 2 clinical trial (NCT01409915) using sargramostim (rhuGM‐CSF) in mild‐to‐moderate AD participants (Potter et al., 2021). Thus, we hypothesized the GM‐CSF might also reduce amyloid, prevent pancreatic apoptosis, and thereby reduce blood glucose in the hIAPP mouse model of T2D. Method We investigated GM‐CSF treatment effects in hIAPP mice (Jackson strain Tg(Ins2‐IAPP)RHFSoel), which accumulate amylin amyloid in pancreatic islets. Hemizygous mice received daily subcutaneous injections (5 days/week for 23 total injections) of either recombinant murine GM‐CSF (5 µg/day or ∼167 µg/kg) or sterile saline, and were then euthanized, perfused according to CU Anschutz OLAR regulations, and pancreatic tissues obtained and processed for histopathology. Contrastingly, homozygous mice received 15 total injections and were monitored for 45 days post‐treatment, before euthanizing and perfusion procedures. In homozygous mice, blood glucose levels were measured 3 days/week (weeks 2‐4) and at 45 days post‐treatment. Unpaired t‐tests were used to determine significant differences (p<0.05) between treatment groups. Result In pancreas of male GM‐CSF‐treated hemizygous mice (n = 9), Thioflavin‐S staining revealed significantly less pancreatic amyloid (p = 0.0140) and Caspase‐3 immunohistochemistry showed significantly less apoptosis (p = 0.0057), compared to the saline‐treated group (n = 7). In homozygous mice, GM‐CSF‐treated male (n = 5) and female (n = 3) mice showed significantly reduced blood glucose from baseline levels, which treatment effects were sustained 45 days post‐treatment (p<0.001 female, p = 0.0002 combined M/F), whereas saline treatments (n = 5 male; n = 3 female) had no effect. Conclusion These preliminary data suggest therapeutic potential for GM‐CSF to prevent or treat T2D, and thereby reduce AD risk.