Involvement of insulin receptor substrates in cognitive impairment and Alzheimer’s disease

Abstract

Type 2 diabetes—associated with impaired insulin/insulin-like growth factor-1 (IGF1) signaling (IIS)—is a risk factor for cognitive impairment and dementia including Alzheimer’s disease (AD). The insulin receptor substrate (IRS) proteins are major components of IIS, which transmit upstream signals via the insulin receptor and/or IGF1 receptor to multiple intracellular signaling pathways, including AKT/protein kinase B and extracellular-signal-regulated kinase cascades. Of the four IRS proteins in mammals, IRS1 and IRS2 play key roles in regulating growth and survival, metabolism, and aging. Meanwhile, the roles of IRS1 and IRS2 in the central nervous system with respect to cognitive abilities remain to be clarified. In contrast to IRS2 in peripheral tissues, inactivation of neural IRS2 exerts beneficial effects, resulting in the reduction of amyloid β accumulation and premature mortality in AD mouse models. On the other hand, the increased phosphorylation of IRS1 at several serine sites is observed in the brains from patients with AD and animal models of AD or cognitive impairment induced by type 2 diabetes. However, these serine sites are also activated in a mouse model of type 2 diabetes, in which the diabetes drug metformin improves memory impairment. Because IRS1 and IRS2 signaling pathways are regulated through complex mechanisms including positive and negative feedback loops, whether the elevated phosphorylation of IRS1 at specific serine sites found in AD brains is a primary response to cognitive dysfunction remains unknown. Here, we examine the associations between IRS1/IRS2-mediated signaling in the central nervous system and cognitive decline.

Exendin-4 improves long-term potentiation and neuronal dendritic growth in vivo and in vitro obesity condition

“…In metabolic imbalance conditions such as obesity, IRS-1 dysregulation leads to insulin resistance in the brain and results in neuropathological problems 54 . Several studies have demonstrated that insulin resistance by IRS-1 and IRS-2 dysregulation in the brain causes onset of neurodegenerative disease and results in cognitive decline 54 , 56 . Serine phosphorylation of IRS-1 elevates amyloid beta accumulation and exacerbates memory deficit in AD brain 57 .…”

Genetic Base of Behavioral Disorders in Mucopolysaccharidoses: Transcriptomic Studies

“…The obvious consequence of this receptor deficit is diabetes [34], the disorder that often occurs also in MPS patients, particularly in MPS III, and in fact, impaired expression of INSR is evident in cells from patients suffering from all MPS III subtypes. However, impaired functions of IGF1 (insulin/insulin-like growth factor) signaling, which includes insulin receptor substrates, have been recognized as a risk factor for dementia and cognitive impairment [35]. Therefore, one might speculate that decreased levels of the insulin receptor may facilitate development of such symptoms in neuronopathic forms of MPS.…”

Insulin Resistance at the Crossroad of Alzheimer Disease Pathology: A Review

“…This TNF-α counter-insulinic effect, in which the insulin receptor becomes inactivated by increasing the inhibitory phosphorylation threshold of the IRS1, has been broadly described in diabetes (128) and in neurons presenting Tau-pathology and NFT (129). These IRS inhibitory phosphorylations described in AD patients' brains and transgenic mice lead to IR states (34), memory declines, and cognitive impairment (130).…”