Intracranial Transplantation of Pancreatic Islets Attenuates Cognitive and Peripheral Metabolic Dysfunctions in a Rat Model of Sporadic Alzheimer's Disease.

ABSTRACT

BACKGROUND: Alzheimer's disease (AD) is often associated with brain insulin resistance and peripheral metabolic dysfunctions. Recently, we developed a model of sporadic AD associated with obesity-related peripheral metabolic abnormalities in Lewis rats using intracerebroventricular administration of streptozotocin (icv-STZ). OBJECTIVE: We aimed to assess the effect of intracranially grafted pancreatic islets on cognitive and peripheral metabolic dysfunctions in the icv-STZ Lewis rats. METHODS: AD-like dementia associated with obesity was induced in inbred Lewis rats using a single icv-STZ. Two months after icv-STZ, syngeneic islets (100 islets per recipient) were implanted in the cranial subarachnoid cavity of icv-STZ rats. Morris water maze and marble burying tests were used for studying cognitive and behavioral functions. Central and peripheral metabolic alterations were assessed by histological and biochemical assays. RESULTS: The icv-STZ induced increases in food intake, body weight, and blood levels of insulin and leptin without alteration of glucose homeostasis. Grafted islets reduced body weight gain, food consumption, peripheral insulin resistance, and hyperleptinemia. Biochemical and histological analysis of the brain revealed viable grafted islets expressing insulin and glucagon. The grafted islets did not affect expression of brain insulin receptors and peripheral glucose homeostasis. Two months after islet transplantation, cognitive and behavioral functioning in transplanted rats were significantly better than the sham-operated icv-STZ rats. No significant differences in the locomotor activity between transplanted and non-transplanted icv-STZ rats were found. CONCLUSIONS: Intracranial islet transplantation attenuates cognitive decline and peripheral metabolic dysfunctions providing a novel therapeutic approach for sporadic AD associated with peripheral metabolic dysfunctions.