Recent studies have highlighted that
diabetes mellitus (DM) is a strong risk factor for
Alzheimer's disease (AD).
Insulin resistance and/or
hyperinsulinemia is one of the main characteristics of type 2 DM. Numerous epidemiological studies have demonstrated that
insulin resistance contributes to AD pathogenesis. However the molecular mechanisms of association between these still remain elusive. Among the various possible mechanisms, the GSK-3β activity has been reported to be impaired in
insulin-resistance, type 2 DM and AD. Thus, the present study was designed to explore the neuroprotective role of GSK3 β inhibitor,
Indirubin-3'-monoxime (IMX) in
insulin resistance induced
cognitive impairment. Further, we have explored the possible molecular mechanism involved in
cognitive impairment associated with
insulin resistance. The mice subjected to high fat diet exhibited characteristic features of
insulin resistance viz. increased serum
glucose,
triglycerides,
cholesterol,
insulin levels and impaired spatial learning and memory ability along with reduced brain
insulin level, elevated oxidative stress and
acetylcholinesterase (AChE) activity. The observed changes occurred concurrently with reduced
brain derived neurotrophic factor. In contrast, the mice treated with IMX showed a significant reduction in plasma
glucose,
triglycerides,
cholesterol,
insulin levels and improvement in learning and memory performance, attenuated the oxidative stress and AChE activity. Moreover, IMX dose dependently augment the brain
insulin and
BDNF levels in HFD fed mice. Based upon these findings it could be suggested that GSK3 β inhibition could prove to be beneficial in
insulin resistance induced cognitive deficit and this neuroprotection could be the result of enhanced
BDNF based synaptic plasticity.