The cross-talk between NGF and insulin pathways downstream the insulin receptor suggests novel potential therapeutic targets to slow cognitive decline in AD and diabetes-related brain insulin resistance.
While increasing insulin receptor occupation has been successful in offsetting cognitive decline, alternative molecular approaches should be considered as they could bypass the need for brain insulin delivery.
In such a case, it is important to develop pharmacological interventions that directly restore plasma insulin levels, insulin receptor function, and hexokinase activity, thereby avoiding damage to neural tissue that is associated with cognitive deficits in diabetic patients, particularly patients with type-2 diabetes.
In this regard, it is of note that upregulation of plasma adiponectin (APN), a benign adipokine that sensitizes the insulin receptor signaling pathway and suppresses inflammation, has recently been associated with the severities of amyloid deposits and cognitive deficits in the elderly, suggesting that APN may enhance the risk of AD.
Since IR expression is diminished in type-2 diabetes as well as in Alzheimer's disease (AD) patients, these data may provide a mechanistic link between insulin resistance, impaired synaptic transmission and cognitive decline in humans with metabolic disorders.
Defective insulin receptor signalings are associated with the dementia in normal aging and patients with age-related neurodegenerative diseases (e.g., Alzheimer's disease); the cognitive impairment can be reversed with systemic administration of insulin in the euglycemic condition.