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Open AccessArticle

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

1
Department of Integrative Aging Neuroscience, National Center for Geriatrics and Gerontology, Obu, Aichi 474-8511, Japan
2
Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Wako, Saitama 351-0106, Japan
3
Department of Neurocognitive Science, Nagoya City University Graduate School of Medical Science, Nagoya, Aichi 467-8601, Japan
*
Author to whom correspondence should be addressed.
These authors contributed equally.
Nutrients 2019, 11(8), 1942; https://doi.org/10.3390/nu11081942
Received: 23 July 2019 / Revised: 3 August 2019 / Accepted: 14 August 2019 / Published: 17 August 2019
(This article belongs to the Special Issue Nutrition and Central Nervous System)
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. View Full-Text
Keywords: IRS1; serine phosphorylation; hippocampus; diabetes; aging; Alzheimer’s disease; memory decline; Aβ; AMPK; energy depletion IRS1; serine phosphorylation; hippocampus; diabetes; aging; Alzheimer’s disease; memory decline; ; AMPK; energy depletion
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Wang, W.; Tanokashira, D.; Fukui, Y.; Maruyama, M.; Kuroiwa, C.; Saito, T.; Saido, T.C.; Taguchi, A. Serine Phosphorylation of IRS1 Correlates with Aβ-Unrelated Memory Deficits and Elevation in Aβ Level Prior to the Onset of Memory Decline in AD. Nutrients 2019, 11, 1942.

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