Role Of Integrin-Linked Kinase In Synaptic Plasticity And Memory:o Diabetes/Alzheimer’s Link

Abstract

Type 2 diabetes mellitus (T2DM) has recently been proven to be a risk factor for cognitive dysfunction and dementia such as Alzheimer’s disease (AD). However, the exact pathophysiology of cognitive dysfunction in patients who suffer T2DM remain to be clearly defined. Our recent study using intracerebroventricular streptozocin (ic. STZ)-injected rats- a model of sporadic AD with central insulin resistance and brain insulin deficiency revealed that hippocampal synaptic impairments and deficits in long term potentiation (LTP - a cellular model of memory), correlated well with alterations in integrin linked kinase (ILK) signaling, a serine-threonine kinase that functions downstream of growth factor and β-integrin receptors to regulate cell growth and differentiation. However, a causal link between ILK, synaptic transmission and plasticity has not yet been investigated. In the current study, inhibition of ILK activity by using a potent and specific pharmacological modulator resulted in impaired synaptic transmission and plasticity in the hippocampus. Additionally, induction of chemical LTP (cLTP) in organotypic hippocampal slice cultures enhanced ILK activity. Taken together, this study demonstrated for the first time, an essential role of ILK in hippocampal synaptic transmission and plasticity required for information storage (memory) in the brain. A Recent study reported that phosphatase and tensin homolog (PTEN), a negative modulator of ILK activity, is upregulated in the fat tissue of T2DM patients and type 2 diabetic mouse model db/db mice. In addition, studies demonstrated that activation of the nuclear hormone receptor, peroxisome proliferator-activated receptor (PPAR) delta, modulates PTEN activity and enhance ILK expression and activity. PPAR delta agonists have been recently proven to exert neuroprotective effects in experimental models of AD. However, it remains unclear if activation of PPAR delta will improve cognitive dysfunction caused by type II diabetes. Therefore, in view of the abobe findings and due to wide spread prevalence of PPAR delta in the brain, we investigated the effect of high affinity PPAR delta agonist GW0742 on hippocampal long-term potentiation and spatial memory in the type II diabetic animal model db/db/ mice. Our findings suggest that molecular targets such as PPAR delta may offer potential therapeutic targets for cognitive dysfunction in patients with T2DM.