α-Enolase reduces cerebrovascular Aß deposits by protecting Aß amyloid formation.

Cerebral amyloid angiopathy (CAA) is characterized by cerebrovascular amyloid ß (Aß) deposits and causes dementia and cerebral hemorrhage. Although α-enolase (ENO1) was shown to possess multifunctional roles, its exact functions in CAA pathogenesis have not been determined. In this study, we focused on ENO1, a well-known glycolytic enzyme, which was previously identified via a proteomic approach as an upregulated protein in brain samples from patients with Alzheimer's disease (AD). We utilized the thioflavin T fluorescence assay and transmission electron microscopy to monitor the effects of ENO1 on amyloid formation by Aß peptides. We also cultured murine primary cerebrovascular smooth muscle cells to determine the effects of ENO1 on Aß cytotoxicity. To investigate the effects of ENO1 in vivo, we infused ENO1 or a vehicle control into the brains of APP23 mice, a transgenic model of AD/CAA, using a continuous infusion system, followed by a cognitive test and pathological and biochemical analyses. We found that novel functions of ENO1 included interacting with Aß and inhibiting its fibril formation, disrupting Aß fibrils, and weakening the cytotoxic effects of these fibrils via proteolytic degradation of Aß peptide. We also demonstrated that infusion of ENO1 into APP23 mouse brains reduced cerebrovascular Aß deposits and improved cognitive impairment. In addition, we found that enzymatically inactivated ENO1 failed to inhibit Aß fibril formation and fibril disruption. The proteolytic activity of ENO1 may thus underlie the enzyme's cytoprotective effect and clearance of Aß from the brain, and ENO1 may be a therapeutic target in CAA.