Brain insulin resistance: an early risk factor for Alzheimer's disease development in Down syndrome

Abstract

Down syndrome (DS) is the most frequent chromosomal abnormality that causes intellectual disability, resulting from the presence of an extra complete or segment of chromosome 21 (HSA21) (Tramutola et al., 2020; Lanzillotta et al., 2021). Every year, approximately 6000 children are born with DS and most of them do not have an autonomous life. Thanks to the advancement in medical care, DS individuals live long and often outlive their parents (Lott and Head, 2019). As a consequence, individuals with DS are now experiencing a high incidence of age-associated health problems, especially Alzheimer's disease (AD) dementia (Lott and Head, 2019). In particular, by the age of 40 years, virtually all individuals with DS show AD neuropathology (Lott and Head, 2019). The link between AD and DS is thought to be mainly related to the triplication of the amyloid precursor gene (APP), which is encoded on HSA21. However, trisomy of HSA21 results in increased gene dosage for other genes in addition to APP, which may also be involved in AD development. These include superoxide dismutase 1, which is involved in redox metabolism; adenosine triphosphate (ATP)-binding cassette sub-family G member 1, which is involved in cholesterol metabolism; cystatin B, beta-secretase 2, and synaptojanin 1 involved in beta-amyloid (Aβ) processing and clearance; the dual-specificity tyrosine phosphorylation-regulated kinase-1A, which is involved in Tau phosphorylation; regulator of calcineurin, which is involved in mitochondrial dysfunction; S100B involved in inflammatory responses (Lott and Head, 2019). In addition to the above-mentioned mechanisms, another potential pathway of AD pathogenesis in DS is represented by the dysregulation of brain insulin signaling (Tramutola et al., 2020; Lanzillotta et al., 2021). Indeed, molecules regulating glucose metabolism, i.e., insulin, are being widely investigated due to their impact on learning and memory, brain development, and aging (Arnold et al., 2018). Brain insulin resistance is referred to as an inadequate response to insulin by brain cells. Interestingly, an increased accumulation of markers for brain insulin resistance was observed early in AD, and brain insulin resistance seems to greatly contribute to the long preclinical period during which often only subtle symptoms are evident in AD (Arnold et al., 2018). Brain insulin resistance impairs synaptic integrity, and Aβ and Tau can also interfere with the actions of insulin at the synapse (Arnold et al., 2018). To note, both synaptic compromise and brain insulin resistance are thought to be present at the earliest stages of AD (Arnold et al., 2018). Mechanistically, brain insulin resistance is due to the downregulation of insulin receptor (IR) or a faulty activation of the insulin signaling cascade mainly driven by the insulin receptor substrate 1 (IRS1) inhibition (Arnold et al., 2018) (Figure 1). Indeed, IR downregulation reduces the pool of IR protein at the level of the plasma membrane available to bind insulin. Rather, the inhibition of IRS1 – mediated by the phosphorylation of specific serine residues (307, 312, 636) – leads the uncoupling of IRS1 from the IR, finally responsible for the inability of insulin to promote its downstream effects (Arnold et al., 2018).Figure 1: Schematic representation of insulin signaling pathway with highlighted proteins found to be altered in DS brain.Under physiological conditions, binding of insulin to the insulin receptor (IR) leads to IR autophosphorylation on Tyr residues (e.g., Tyr1158/1162/1163), which regulate IR activation. In turn, once activated, IR promotes the phosphorylation of its substrate (insulin receptor substrate-1, IRS1) on specific Tyr residues (e.g., 632). This event drives the activation of the phosphoinositide 3-kinase/Akt (PI3K-Akt) pathways downstream from IRS1. Akt promotes the phosphorylation of several targets, among which are: (1) Akt substrate of 160 (AS160) (on Thr642, activating site) that together with the atypical protein kinase C zeta (PKC), are responsible for the translocation of glucose transporter-4 (GLUT4)-containing vesicles to the plasma membrane to mediate glucose uptake; (2) Hexokinase-II (HKII) a rate-limiting enzyme involved in glucose metabolism and mitochondrial functions; (3) Glycogen synthase kinase 3 beta (GSK3) (on Ser9, inhibitory site), which has a role in energy production; and (4) the mammalian target of rapamycin (mTOR) (on Ser2448, activating site), which regulates protein synthesis and autophagy. Under pathological conditions, IRS1 can be phosphorylated on Ser residues (e.g., Ser307 and Ser636) and this event is responsible for the uncoupling between IR and IRS1. This molecular event is at the base of the insulin resistance phenomenon and means that even if insulin can bind to IR, this latter is not able to promote IRS1 activation. Hence, pathways downstream from IRS1 cannot be activated in response to insulin. Brain insulin resistance is further as