Intranasal Insulin Reduces White Matter Hyperintensity Progression in Association with Improvements in Cognition and CSF Biomarker Profiles in Mild Cognitive Impairment and Alzheimer's Disease.

BACKGROUND: Intranasally administered insulin has shown promise in both rodent and human studies in Alzheimer's disease; however, both effects and mechanisms require elucidation. OBJECTIVE: We assessed the effects of intranasally administered insulin on white matter health and its association with cognition and cerebral spinal fluid biomarker profiles in adults with mild cognitive impairment or Alzheimer's disease in secondary analyses from a prior phase 2 clinical trial (NCT01767909). DESIGN: A randomized (1:1) double-blind clinical trial. SETTING: Twelve sites across the United States. PARTICIPANTS: Adults with mild cognitive impairment or Alzheimer's disease. INTERVENTION: Participants received either twice daily placebo or insulin (20 IU Humulin R U-100 b.i.d.) intranasally for 12 months. Seventy-eight participants were screened, of whom 49 (32 men) were enrolled. MEASUREMENTS: Changes from baseline in global and regional white matter hyperintensity volume and gray matter volume were analyzed and related to changes in cerebral spinal fluid biomarkers, Alzheimer's Disease Assessment Scale-Cognition, Clinical Disease Rating-Sum of Boxes, Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale, and a memory composite. RESULTS: The insulin-treated group demonstrated significantly reduced changes in white matter hyperintensity volume in deep and frontal regions after 12 months, with a similar trend for global volume. White matter hyperintensity volume progression correlated with worsened Alzheimer's disease cerebral spinal fluid biomarker profile and cognitive function; however, patterns of correlations differed by treatment group. CONCLUSION: Intranasal insulin treatment for 12 months reduced white matter hyperintensity volume progression and supports insulin's potential as a therapeutic option for Alzheimer's disease.

Myeloid expression of the AP-1 transcription factor JUNB modulates outcomes of type 1 and type 2 parasitic infections.

Activation of macrophages is a key step in the initiation of immune responses, but the transcriptional mechanisms governing macrophage activation during infection are not fully understood. It was recently shown that the AP-1 family transcription factor JUNB positively regulates macrophage activation in response to Toll-like receptor agonists that promote classical or M1 polarization, as well as to the cytokine interleukin-4 (IL-4), which elicits an alternatively activated or M2 phenotype. However, a role for JUNB in macrophage activation has never been demonstrated in vivo. Here, to dissect the role of JUNB in macrophage activation in a physiological setting, mice lacking JUNB specifically in myeloid cells were tested in two infection models: experimental cerebral malaria, which elicits a pathological type 1 immune response, and helminth infection, in which type 2 responses are protective. Myeloid-restricted deletion of Junb reduced type 1 immune activation, which was associated with reduced cerebral pathology and improved survival during infection with Plasmodium berghei. Myeloid JUNB deficiency also compromised type 2 activation during infection with the hookworm Nippostrongylus brasiliensis, leading to diminished cytokine production and eosinophil recruitment and increased parasite burden. These results demonstrate that JUNB in myeloid cells shapes host responses and outcomes during type 1 and type 2 infections.