AbstractBackgroundPeople with Type II diabetes mellitus (T2D) are at higher risk for developing Alzheimerâs disease (AD). T2D is characterized histopathologically by the accumulation of fibrillary amyloid deposits in the pancreas, which are comprised primarily of human islet amyloid polypeptide (hIAPP), also known as amylin. Amylin, which selfâaggregates in a manner similar to amyloid beta, has been implicated as a source of pathogenesis in both T2D and AD. In T2D patients, pancreatic amyloid deposition occurs before and induces islet βâcell apoptosis.Granulocyteâmacrophage colonyâstimulating factor (GMâCSF) has demonstrated antiâapoptotic, neuroprotective, neurotrophic, immunomodulatory, and regenerative effects in several neuronal injury models. We discovered that GMâCSF 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 (rhuGMâCSF) in mildâtoâmoderate AD participants (Potter et al., 2021). Thus, we hypothesized the GMâCSF might also reduce amyloid and prevent cell death in the pancreas of the hIAPP mouse model of T2D.MethodWe investigated GMâCSF treatment effects in 12âweekâold male hemizygous hIAPP mice (Jackson strain Tg(Ins2âIAPP)RHFSoel), which accumulate amylin amyloid in pancreatic islets. Mice received daily subcutaneous injections (5 days/week for 23 total injections) of either recombinant murine GMâCSF (5 Âľg/day or âź167 Âľg/kg; n=9) or sterile saline (n=7), and the animals were then euthanized, perfused according to CU Anschutz OLAR regulations, and pancreatic tissues were obtained and processed for histopathology. Whole blood samples were obtained before perfusion, and blood chemistry analyses were performed for T2D biomarker levels (BUN, amylase, LDH, glucose, ALT). Unpaired tâtests were used to determine significant differences (p<0.05) between treatment groups.ResultThioflavinâS staining revealed significantly less pancreatic amyloid (p=0.00114, saline n=3, GMâCSF n=7) and Caspaseâ3 immunohistochemistry showed significantly less apoptosis (p=0.0057, Saline n=7, GMâCSF n=9) in pancreatic tissue from the GMâCSFâtreated group. There were no significant differences observed for the blood chemistry biomarkers, but trends were observed for lower levels of BUN and higher levels of amylase in the GMâCSFâtreated group.ConclusionThese preliminary data suggest a therapeutic potential for GMâCSF to prevent or treat T2D, and thereby reduce AD risk.