Abstract
The insulin/IGF-1 signaling (IIS) regulates a wide range of biological processes, including aging and lifespan, and has also been implicated in the pathogenesis of Alzheimer's disease (AD). We and others have reported that reduced signaling by genetic ablation of the molecules involved in IIS (e.g., insulin receptor substrate 2 [IRS-2]) markedly mitigates amyloid plaque formation in the brains of mouse models of AD, although the molecular underpinnings of the amelioration remain unsolved. Here, we revealed, by a transcriptomic analysis of the male murine cerebral cortices, that the expression of genes encoding extracellular matrix (ECM) was significantly upregulated by the loss of IRS-2. Insulin signaling activity negatively regulated the phosphorylation of Smad2 and Smad3 in the brain, and suppressed TGF-β/Smad-dependent expression of a subset of ECM genes in brain-derived cells. The ECM proteins inhibited Aβ fibril formation in vitro, and IRS-2 deficiency suppressed the aggregation process of Aβ in the brains of male APP transgenic mice as revealed by injection of aggregation seeds in vivo Our results propose a novel mechanism in AD pathophysiology whereby IIS modifies Aβ aggregation and amyloid pathology by altering the expression of ECM genes in the brain.SIGNIFICANCE STATEMENT The insulin/IGF-1 signaling (IIS) has been recognized as a regulator of aging, a leading risk factor for the onset of Alzheimer's disease (AD). In AD mouse models, genetic deletion of key IIS molecules markedly reduces the amyloid plaque formation in the brain, although the molecular underpinnings of this amelioration remain elusive. We found that the deficiency of insulin receptor substrate 2 leads to an increase in the expression of various extracellular matrices (ECMs) in the brain, potentially through TGF-β/Smad signaling. Furthermore, some of those ECMs exhibited the potential to inhibit amyloid plaque accumulation by disrupting the formation of Aβ fibrils. This study presents a novel mechanism by which IIS regulates Aβ accumulation, which may involve altered brain ECM expression.