Abstract
The biological effects of insulin signaling are regulated by the phosphorylation of insulin receptor substrate 1 (IRS1) at serine (Ser) residues. In the brain, phosphorylation of IRS1 at specific Ser sites increases in patients with Alzheimer’s disease (AD) and its animal models. However, whether the activation of Ser sites on neural IRS1 is related to any type of memory decline remains unclear. Here, we show the modifications of IRS1 through its phosphorylation at etiology-specific Ser sites in various animal models of memory decline, such as diabetic, aged, and amyloid precursor protein (APP) knock-in NL-G-F (APPKINL-G-F) mice. Substantial phosphorylation of IRS1 at specific Ser sites occurs in type 2 diabetes- or age-related memory deficits independently of amyloid-β (Aβ). Furthermore, we present the first evidence that, in APPKINL-G-F mice showing Aβ42 elevation, the increased phosphorylation of IRS1 at multiple Ser sites occurs without memory impairment. Our findings suggest that the phosphorylation of IRS1 at specific Ser sites is a potential marker of Aβ-unrelated memory deficits caused by type 2 diabetes and aging; however, in Aβ-related memory decline, the modifications of IRS1 may be a marker of early detection of Aβ42 elevation prior to the onset of memory decline in AD.
Highlights
Insulin signaling mediated by insulin receptor substrates 1 and 2 (IRS1 and IRS2) is involved in the regulation of growth, glucose homeostasis, energy metabolism, and lifespan [1,2,3,4]
While mice fed a 60% high-fat diet (HFD) for 17 days and mice or rats fed a 40% HFD for 6–8 weeks exhibited memory impairment accompanied by increased phosphorylation at hSer616/mSer612 or hSer312/mouse Ser307 [p-IRS1 (mSer307) [21,22], 12-week-old diet-induced obesity (DIO) mice fed a 60% HFD for 9 weeks exhibited normal memory function under our experimental conditions (Figure S1), suggesting that changes in neural insulin receptor substrate 1 (IRS1) Ser residues are variable on a temporal scale in DIO mice
These discrepancies may be due to the differences in observation time, animal species, and HFD or STZ. Protocols, such as age, duration of exposure, diet fat content, and drug dosages. These results suggest that the reciprocal effects of the phosphorylation of IRS1 at type 2 diabetes mellitus (T2DM)- or age-related Ser sites and downstream components via feedback loops that may lead to the common alterations in the activity of p70S6K and AMPK are involved in Aβ-unrelated memory decline; the modification of IRS1 through Ser sites is not required for the onset of memory deficits in STZ-induced Type 1 Diabetes Mellitus (T1DM) mice
Summary
Insulin signaling mediated by insulin receptor substrates 1 and 2 (IRS1 and IRS2) is involved in the regulation of growth, glucose homeostasis, energy metabolism, and lifespan [1,2,3,4]. The biological effects of insulin signaling are regulated by the modulation of IRS proteins through serine (Ser) and threonine (Thr) phosphorylation [5,6]. IRS1 is known to be abundantly phosphorylated at Ser and Thr residues regardless of insulin or IGF1 stimulation [5,7]. In vitro studies have demonstrated the relationship between IRS1 Ser/Thr phosphorylation and canonical downstream signaling components, including Akt/protein kinase B, glycogen synthase kinase 3 beta (GSK3β), and ribosomal protein. Under physiological and pathological conditions, Ser/Thr phosphorylation of IRS1 is potentially mediated by multiple kinases, including AMP-activated protein kinase (AMPK), conventional and novel protein kinase C (PKC), and c-Jun N-terminal kinases (JNKs), in response to intracellular energy status, nutritional conditions, and inflammatory stimulation [5,6,8].
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