Extracellular Vesicle Biomarkers Track Cognitive Changes Following Intranasal Insulin in Alzheimer’s Disease

Abstract

Background: Insulin resistance is implicated in Alzheimer’s disease (AD), whereas intranasal insulin is an experimental treatment in clinical trials. We previously proposed insulin signaling mediators in plasma neuronal-enriched extracellular vesicles (EVs) as biomarkers of brain insulin resistance. Objective: We sought to demonstrate the capacity of neuronal-enriched EV biomarkers to demonstrate target engagement in response to intranasal insulin and their ability to track treatment-associated cognitive changes in AD. Methods: We isolated neuronal-enriched EVs from plasma samples of participants with amnestic mild cognitive impairment or probable AD involved in a 4-month duration placebo-controlled clinical trial of 20 or 40IU intranasal insulin. We measured insulin signaling mediators as biomarkers and examined treatment-associated changes and their relationship with cognitive performance (ADAS-Cog). Results: There were no EV biomarker changes from baseline in any of the treatment groups. In participants treated with 20 IU insulin, EV biomarkers of insulin resistance (pS312-IRS-1, pY-IRS-1) showed strong positive correlations with ADAS-Cog changes, especially in ApoE ε4 non-carriers. Conclusion: Neuronal EV biomarkers of insulin resistance (pS312-IRS-1, pY-IRS-1) were associated with cognitive changes in response to low dose intranasal insulin suggesting engagement of the insulin cascade in neurons of origin.

Insulin-signaling abnormalities in drug-naïve first-episode schizophrenia: Transduction protein analyses in extracellular vesicles of putative neuronal origin

“…In line with previous postmortem studies that point to downstream insulin signaling as the primary abnormality [1][2][3], the exploratory analysis of downstream signaling serine-threonine kinases (AKT, GSK3β, mTOR, p70S6K) revealed lower phoshorylated to total protein ratios in patients vs. controls, indicating diminished signaling pathway activity; such a state could result in decreased pS312-IRS-1 via the feedback loops of pGSK3β and p70S6K. In previous nEV studies examining change over time in pS312-IRS-1, AKT, GSK3β, mTOR, and p70S6K in response to interventions, we observed similar direction of change [14,21].…”

“…To gain insight into neuronal insulin-signaling in vivo, we analyzed peripheral blood nEVs which have been considered as a "message in a bottle" from neurons [13], by a well-established protocol used in multiple previous studies [14][15][16][17][18][19][20][21][22][23] and presented in detail in Mustapic et al [5].…”

Extracellular Vesicle Biomarkers Reveal Inhibition of Neuroinflammation by Infliximab in Association with Antidepressant Response in Adults with Bipolar Depression

“…Therefore, any biomarker differences observed cannot be attributed to an infliximab-induced change in NEV load between samples. Previously published work has used EVs to assess changes in biomarkers of brain insulin signaling in clinical trials of a protein restriction diet for prostate cancer [30], exenatide for PD [21], and intranasal insulin for AD [29]. This is the first NEV study focused on a neuro-inflammatory pathway in a mood disorders' population, broadening the scope, and providing further support for the utility of NEVs as outcomes in clinical trials in neurology and psychiatry.…”

“…This methodology has been used to directly assess neuronal inflammatory biomarkers in mild traumatic brain injury [25,26], as well as biomarkers from other pathways in disparate conditions, such as Alzheimer's disease (AD) and schizophrenia [27,28]. In addition, NEVs have been used as a source of biomarkers that predict neuronal-specific molecular target engagement and response to experimental treatments in clinical trials (e.g., in Parkinson's disease [21], AD [29], and cancer [30]), revealing concerted engagement of entire signaling pathways.…”

Extracellular vesicle biomarkers of Alzheimer's disease associated with sub‐clinical cognitive decline in late middle age

“…Dysregulation of insulin signaling might be an early event in AD pathogenesis linked to tau phosphorylation through GSK‐3β activity and other mechanisms 40 . Insulin signaling nEV biomarkers have previously been associated with memory performance across diverse groups (eg, older individuals, 16 patients with schizophrenia 41 ), cortical atrophy in AD, 42 and response to experimental treatments (intranasal insulin in AD, 43 exenatide in PD 44 ). The observed prospective association of p‐IRS‐1 and downstream effectors with memory is concordant with findings of an autopsy study associating their brain expression with ante‐mortem cognition 45 .…”