Objective: The objective of this study was to determine the presence of amylin deposits in the brain of subjects with synucleinopathies.

Background: The link between Parkinson’s disease (PD) and type two diabetes mellitus (T2DM) has long been recognized in epidemiological studies. T2DM is a metabolic disease characterized by beta-cell dysfunction. Amylin is a small and highly amyloidogenic protein, whose aggregation has been implicated in this process. Amylin has also been related to PD pathophysiology since it interacts with alpha-synuclein promoting in vitro alpha-synuclein amyloid formation. We have provided histological evidence of this interaction in the pancreatic tissue of PD patients, and of the presence of amylin aggregates in PD brains.

Method: We evaluated post-mortem brain specimens from PD patients (n=35), and similar aged controls (n=20). Three regions of the brain were examined: frontal cortex, substantia nigra and amygdala. We evaluated both amylin and SNCA mRNA expression levels. Besides, quantification of amylin, alpha-synuclein and phosphorylated alpha-synuclein protein levels was performed by WB and ELISA. We performed serial staining with anti-amylin antibody and Thioflavin S staining. On the other hand, to assess the amyloidogenicity or the “seeding” capacity of the amylin present in the brain, we used a novel RT-QuIC assay designed in our laboratory that enabled us to evaluate the kinetics formation of amylin fibrils with thioflavin T. For the amylin/synuclein interaction assessment we designed and performed two PLA for the detection of amylin/synuclein and amylin/phosphorylated-synuclein interactions.

Results: We found extracellular and cytoplasmic amylin inclusions in the brain of 31 subjects with Parkinson’s disease (88%). We found that both cytoplasmic and extracellular amylin deposits were immunoreactive for thioflavin S staining and RT-QuIC positive. The PLA assays determined that in addition to their co-localization in cells, there was a direct interaction between amylin and synuclein.

Conclusion: The presence of both synuclein inclusions in pancreatic beta cells, and of amylin deposits in the brain, provides new evidence of a potential overlap in the mechanisms underlying the pathogenesis of T2DM and Parkinson’s disease. Moreover, the interaction of amylin with synuclein in pancreatic β cells, and in the brain of patients, may represent a novel target to develop therapies for these diseases

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MDS Abstracts - https://www.mdsabstracts.org/abstract/amylin-deposition-in-the-brain-of-parkinsons-disease-patients/