Marker of Brain Insulin Resistance in AD Prognosis

Overview

Basic research data from the literature on the links between cerebral insulin resistance and Alzheimer's disease (AD) suggest that this pathophysiological mechanism is involved at a very early stage in the development of the disease. The insulin receptor (IR) is a tyrosine kinase receptor whose activation by insulin binding leads to autophosphorylation of its IRβ subunits and then of the insulin receptor substrate proteins (IRS-1). The ratio of IRS residues phosphorylated on serine 312 (P(Ser312)-IRS-1) to total phosphorylated IRS or IRS phosphorylated on its tyrosines has been proposed by some authors as an index of insulin resistance in the brain. IRS-1 proteins can be measured in exosomes, and in particular in neuronal exosomes isolated from plasma. It is therefore conceivable to measure this index in these biological samples specifically derived from neurons and available from a simple blood test, in order to determine whether it could be of prognostic interest in patients with mild cognitive impairment (MCI), in particular by making it possible to identify at an early stage patients who are going to convert to AD.

Basic research data from the literature on the links between cerebral insulin resistance and AD suggest that this pathophysiological mechanism is involved at a very early stage in the development of the disease. The multiple effects of insulin on cerebral bioenergetic regulation, synaptic viability, dendritic spine formation and neurotransmitter turnover, as well as on the clearance and degradation of Aβ peptide, All these factors suggest that dysregulation of insulin signalling pathways in the brain may contribute early on to neurodegeneration in AD, and represent both a therapeutic lever and a source of biomarkers relevant to diagnosis and prognosis (1). Several clinical trials are currently underway to validate the value of insulin administration or the use of drugs that affect insulin receptor sensitivity in the treatment of AD patients (2). Given these arguments in favour of the role of cerebral insulin resistance in the early stages of AD, being able to measure such an index in plasma could prove invaluable in the management of patients. However, it is still difficult to distinguish between peripheral and central origin of the molecules measured, which explains the frequent use of lumbar puncture to diagnose neurological diseases. An alternative strategy could be based on the specific isolation of neuronal exosomes present in the blood. Exosomes are vesicles derived from late endosomes and containing nucleic acids, proteins and lipids. Specific protein markers, such as L1CAM for neurons, enable them to be isolated by immunoaffinity, according to their cellular origin. It is then possible to measure plasma biomarkers whose neuronal origin is certain (4). IRS-1 proteins can be measured in exosomes, and in particular in neuronal exosomes isolated from plasma, but studies on the use of this index in AD are rare. One team of researchers has taken a particular interest in this question, showing that the insulin resistance index is significantly higher in AD patients than in control subjects or those with another neurodegenerative disease (3). A more recent study also showed that, in Alzheimer's subjects, brain volume was positively correlated with the level of IRS-1 phosphorylated on its tyrosine residues, whereas it was negatively correlated with the level of IRS-1 phosphorylated on serine 312 (5). This index in exosomes has also been proposed to distinguish good from poor responders to insulin treatment (6) or to illustrate the links between amyloid and Tau pathologies in AD (7). To date, no study has proposed using this index in plasma neuronal exosomes as a marker of conversion to AD in patients with mild cognitive impairment.