Differential involvement of insulin receptor substrate (IRS)-1 and IRS-2 in brain insulin signaling is associated with the effects on amyloid pathology in a mouse model of Alzheimer's disease

• DOI: 10.1016/j.nbd.2021.105510
• Publication Date: 2021-09-16T15:37:50Z
• Authors: Toshitaka Ochiai; Toshiharu Sano; Takeru Nagayama; Naoto Kubota; Takashi Kadowaki; Tomoko Wakabayashi; Takeshi Iwatsubo
• Keywords: Insulin-degrading enzyme; IRS1; Amyloid (mycology)

Insulin signaling has been implicated in the metabolism as well aging and longevity. Type 2 diabetes mellitus its core pathology, insulin resistance, also development of Alzheimer's disease (AD) amyloid-β deposition humans. By contrast, genetic ablation insulin/IGF-1 (IIS) pathway components, e.g. receptor substrate (IRS)-2, documented to suppress accumulation brains transgenic mice overexpressing AD mutant β-amyloid precursor protein (APP). Therefore, brain IIS may be a key modifiable molecular target pathophysiology AD. IRS-1 IRS-2 are critical nodes substrates for IGF-1 receptor, although functional differences between adult yet explored. To examine their relative contribution activity pathomechanism, we generated APP lacking either or IRS-2. deficiency had little effects on associated with compensatory activation IRS-2, whereas was not fully compensated by IRS-1, downstream Akt significantly compromised. Pathological analyses cortical tissues showed that biochemical levels soluble insoluble amyloid-β, histopathology, tau phosphorylation were affected absence contrast marked alteration deleted mice. These results suggest predominance IIS, support hypothesis reduced exerts anti-amyloid brain.