Insulin-resistant brain state: The culprit in sporadic Alzheimer's disease?

Severe abnormalities in brain glucose/energy metabolism and insulin signaling have been documented to take a pivotal role in early sporadic Alzheimer's disease (sAD) pathology. Indeed, the “insulin-resistant brain state” has been hypothesized to form the core of the neurodegenerative events that occur in sAD. In this vein, intracerebroventricular administration of subdiabetogenic doses of streptozotocin (STZ) in rats can induce an insulin-resistant brain state, which is proposed as a suitable experimental model of sAD. This review highlights the involvement of disturbed brain insulin metabolism in sAD etiopathogenesis. Furthermore, current knowledge demonstrates that central STZ administration produces brain pathology and behavioral changes that resemble changes found in sAD patients. The STZ-intracerebroventricularly treated rat represents a promising experimental tool in this field by providing new insights concerning early brain alterations in sAD, which can be translated in novel etiopathogenic and therapeutic approaches in this disease.

Research highlights
► Impairments in brain insulin has been suggested to be involved in the development of Alzheimer disease.
► Characteristics of Alzheimer disease, specifically altered brain glucose metabolism, have led to the development of the hypothesis that this “insulin-resistant brain state” is responsible for biochemical changes and cognitive dysfunction that are features of the disease.
► Further, in diabetogenic animal models using streptozotocin which induces glucose metabolic changes, there is demonstrable and progressive learning and memory loss, similar to the clinical changes found with Alzheimer disease.
► Finally, this model may provide a useful tool for studying and targeting the pathological and clinical impairments relating to amyloid formation, tau phosphorylation, and glucose metabolism.