**Serine Phosphorylation of IRS1 Correlates with A**β**-Unrelated Memory Deficits and Elevation in A**β **Level Prior to the Onset of Memory Decline in AD**

**Wei Wang 1,**†**, Daisuke Tanokashira 1,**†**, Yusuke Fukui 1, Megumi Maruyama 1, Chiemi Kuroiwa 1, Takashi Saito 2,3, Takaomi C. Saido <sup>2</sup> and Akiko Taguchi 1,\***


Received: 23 July 2019; Accepted: 14 August 2019; Published: 17 August 2019

**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.

**Keywords:** IRS1; serine phosphorylation; hippocampus; diabetes; aging; Alzheimer's disease; memory decline; Aβ; AMPK; energy depletion
