Role of Insulin Resistance in the Development of Alzheimer-like Symptoms in a Transgenic Mouse Model

Abstract

The relationship between Alzheimer’s disease (AD) and type 2 Diabetes has been demonstrated in many studies but remains to be thoroughly examined. Poorly controlled hyperglycemia has been shown to increase the risk of developing AD. This association is so strong that some have called AD the “neuro-endocrine disorder”, or “type 3 diabetes (T3D)”. Type 3 Diabetes mellitus (T3DM) consists of a chronic insulin resistance in nerve cells accompanied by insulin deficiency. In this study, we aimed to further investigate the role of insulin resistance associated with type 2 diabetes in the development of AD-like symptoms and pathologies in rodents.

All experimental procedures were conducted in accordance with the ethical guidelines and under the approval of the Institutional Animal Care and Use Committee (IACUC) of the American University of Beirut (AUB). Male MKR transgenic mice and their control (FVB mice) were used in this study. Animals were divided into three groups. One group was fed normal diet and the other with high fat diet. A third group of FVB mice was injected with an amyloid beta solution into the lateral ventricle to assess the symptoms of AD. Sensory and cognitive functions were evaluated in all mice prior to and monthly for 3 months using a battery of behavioral and immunohistochemical tests.

Cognitive functions in all mice were evaluated using the T-maze test for spatial memory, and the cheese board maze test for memory recognition. On the other hand, sensitivity to thermal stimulation was measured using the heat hyperalgesia test. Immunohistochemical staining of brain tissues was performed to detect the deposition of β-amyloid peptides. Compared to the control group, both MKR mice and Amyloid-beta injected mice showed deposition of amyloid beta protein in their brain tissues, concomitant with impaired cognitive abilities in both T-maze and cheeseboard maze, and reduced sensory functions. Collectively, our data indicate that Type-2 diabetes and insulin resistance significantly contribute to the sensory and cognitive decline and development of symptoms characteristic of Alzheimer’s disease.