Repurposing peripheral immunocytes of Bacillus Calmette Guerin-vaccinated melanoma patients to reveal preventive Alzheimer's disease mechanisms, possibly via the unfolded protein response.

Abstract

Background: Alzheimer's disease (AD) dysfunctional unfolded protein response (UPR) is revealed by amyloid-β aggregates. Normally, UPR reacts to endoplasmic reticulum stress by resolving misfolded/aggregated proteins, and UPR failure induces brain-cell apoptosis consistent with AD pathology. Peripheral blood mononuclear cells (PBMC) and immunocyte brain infiltrates are involved in AD pathogenesis, whose risk is lowered by the Bacillus Calmette Guerin (BCG) vaccine. Hypothetically, BCG prevents AD caused by UPR-driven apoptosis in PBMC brain infiltrates, corrected by BCG-vaccinated PBMC brain infiltrates.

Objective: To reveal whether BCG shifts the UPR towards cell survival. Method: PBMC proteins from 6 individuals were compared by immuno-electrophoresis before and after BCG hypervaccination. Cryopreserved PBMC provided an opportunity to analyze the BCG impact on the UPR, although their donor destiny to develop AD was unknown. UPR signaling responsive to BCG was recorded to examine if BCG can influence UPR signaling and thereby explain the previously demonstrated AD prevention by BCG.

Results: UPR signal levels were scored according to positive versus negative cell survival odds by the BCG impact on a dozen UPR signals. The balance between positive and negative scores of individuals emphasizes the impact of the BCG vaccine on the UPR. The antiapoptotic UPR signals under BCG show opposite trends to UPR signals in AD brains, reported by the literature. In conclusion, 3/6 individuals had superior PBMC survival chances under BCG.

Conclusions: These results suggest that the UPR is part of the mechanism responsible for reducing the risk of AD, as previously shown among BCG-treated bladder cancer patients.