Editorial: Brain Insulin Resistance in Neurodevelopmental and Neurodegenerative Disorders: Mind the Gap!

Abstract

Editorial on the Research Topic Brain Insulin Resistance in Neurodevelopmental and Neurodegenerative Disorders: Mind the Gap!The failure of insulin signaling-a condition known as insulin resistance-is a key pathological feature of both type 2 diabetes (T2DM, systemic insulin resistance) (Arnold et al., 2018;Kellar and Craft, 2020) and brain disorders, such as Alzheimer disease and related dementias (ADRDs, brain insulin resistance) but also other neurodegenerative disorders such as Parkinson's or Huntington's disease (Brás et al., 2019;Hong et al., 2020), neurodevelopmental disorders such as Down syndrome (DS) (Tramutola et al., 2020;Lanzillotta et al., 2021) or autism (Manco et al., 2021) and behavioral disorders (Kleinridders et al., 2015), and greatly contributes to their pathogenesis (Arnold et al., 2018;Kellar and Craft, 2020). Specifically, regarding ADRDs and T2DM, considerable overlap has been found in the risk factors, comorbidities and putative pathophysiological mechanisms, leading to the proposal that AD is type 3 diabetes (Butterfield et al., 2014;de la Monte, 2019). Examination of postmortem AD, amnestic mild cognitive impairment and DS brains, uncovered key signs of brain insulin resistance, i.e., reduced insulin receptor (IR) and increased serine phosphorylation (inhibitory) of insulin receptor substrate 1 (IRS1), as well as reduced activation of pathways downstream from IRS1, particularly in the hippocampus, cortex, and hypothalamus (Talbot et al., 2012;Tramutola et al., 2015Tramutola et al., , 2020Sharma et al., 2019). Higher levels of insulin resistance markers are associated with poorer performance on cognitive tests of episodic and working memory, independent of the load of senile plaques and tangles, thus suggesting a role for insulin signaling in neuronal functions (Talbot et al., 2012). At the cellular level, these dysfunctions might manifest as the impairment of neuroplasticity, receptor regulation or neurotransmitter release in neurons (

The Molecular Mechanisms of the Relationship between Insulin Resistance and Parkinson’s Disease Pathogenesis

“…Insulin is involved in the maintenance of brain homeostasis and its physiological functions. Hence, defective insulin signaling could contribute to PD development [ 5 , 28 ]. Also, α-synuclein aggregation in the nigrostriatal system has been observed in hyperglycemic mice models, suggesting an association between hyperglycemia and PD development [ 29 ].…”