1813-P: An Experimental Model to Combat the Increased Prevalence of Diabetes in Alzheimer’s Disease

Abstract

Alzheimer’s disease is associated with many other disorders of healthful aging; one of the most prominent is the increased prevalence of diabetes in patients with Alzheimer’s, resulting in almost twice the number of hospitalizations compared with that of non-Alzheimer’s patients. The goal of this investigation was to discover an animal model that was protected both from Alzheimer’s Disease and diabetes. The adenylyl cyclase type 5 (AC5) knockout (KO) was selected since it not only lives a third longer than its wild type (WT), but is also a model of healthful aging, with improved metabolism, enhanced exercise capacity and protection against obesity and diabetes. Accordingly, we compared the AC5 KO with that of the J20 mouse, a model for Alzheimer’s disease. Comparisons were made among AC5 KO, J20 and WT mice for behavioral tests indicative of Alzheimer’s and diabetes protection as reflected by the glucose tolerance test. All 3 behavioral tests studied demonstrated that AC5 KO were protected compared to WT, whereas the J20 mice demonstrated behavioral alterations consistent with Alzheimer’s Disease. For example, the water maze test, used to assess spatial learning and memory, demonstrated the expected 134± 7.6% deficit, p<0.05, in the J20 mice, in contrast to the 38± 3.0% improvement, in performance, p<0.05, in AC5 KO. The glucose tolerance test (GTT) also demonstrated protection in AC5 KO and impaired GTT in the J20 mice, i.e., the area under the curve following 1g/kg IP glucose, was 47± 5.2% less, p<0.05, in AC5 KO compared to WT, whereas it was 137± 10.2% higher, p<.05, than WT in the J20 mice. Thus, the AC5 KO mice were protected both against impaired GTT and behavioral changes associated with Alzheimer’s disease, suggesting that inhibition of AC5 would be a novel therapeutic modality, not only for diabetes, but also for the diabetes associated with Alzheimer’s Disease. Disclosure D. Babici: None. J. Zhang: None. M. Oydanich: None. K. Nishimura: None. D.E. Vatner: None. M. Mouradian: None. S.F. Vatner: None. Funding National Institutes of Health (R01HL102472, R01HL106511, R01HL119464, R01HL124282, R01HL130848, R01HL137368, R01HL137405, R21AG053514)