CROCUS SATIVUS STIGMA EXTRACT IMPROVES AMYLOID-B DEGRADATION IN MONOCYTES FROM ALZHEIMER'S DISEASE PATIENTS

Abstract

Background: Alzheimer’s disease (AD) is characterized by cognitive decline and hallmark neuropathologies, including b-amyloid (Ab). Therapeutic strategies for AD focus on reducing the production or deposition of Ab. Canines develop Ab neuropathology and cognitive decline with age similar to AD patients, making them a useful model for testing potential therapies. Immunization with Ab1-42 (IMM)in aged canines significantly decreases brain Ab and maintains executive function. However, behavioral enrichment (BEH) improves cognition without reducing brain Ab. We hypothesized that IMM combined with BEH would provide larger cognitive benefits and further reduce neuropathology, as compared to controls or individual IMM and BEH treatments alone. Methods: Aged beagles (10.513.6 y) were placed into groups: control (Alum adjuvant only), fibrillar Ab1-42 + Alum vaccine, BEH with Alum, and combination treatment (IMM+BEH). Animals were treated for 18 months. Cognition was measured throughout the study using various learning and memory tasks. Serum IgG antibody titers, cerebral spinal fluid (CSF) Ab levels, and insoluble brain Ab (formic acid extracted) were measured by ELISA. Ab plaque load (6E10, anti-Ab 1-42, Pyro Glu3), CAA (congo red), and microhemorrhages (prussian blue) were measured by immunohistochemistry. Results: Anti-Ab1-42 IgG responses in IMM animals increased significantly and were maintained. BEH significantly increased CSF Ab1-40, while no systematic effects were seen on Ab1-42 or total Ab. IMM significantly reduced both insoluble Ab1-40 and 1-42, as well as all forms of measured plaque load. An overall reduction in 6E10, and Ab 1-42 plaque load due to BEH was also seen. A significant additive affect from BEH and IMM was seen in clearance of Ab 1-42 plaque load. Conclusions: IMM successfully induced an immune response in treated animals and was maintained. IMM significantly reduced all forms of Ab pathology. Additionally, BEH increased CSFAb 1-40 and reduced 6E10 and Ab 1-42 plaque loads. A significant additive effect from BEH and IMM was seen in clearance of Ab 142 plaque load. While changes in cognition, CAA and microhemorrhages remain to be analyzed, it is expected that levels of CAA and microhemorrhages will be lower in IMM animals, and IMM+BEH will show greatest cognitive benefits.