Abstract
We investigated the contents of the insulin receptor-beta subunit (IRβ) and [Tyr1162/1163]-phosphorylated IRβ as surrogate indices of total IR content and IR activation in postmortem hippocampal formation brain specimens from nondiabetic sporadic Alzheimer's disease (AD) cases. We found no significant changes in the brain contents of total IRβ or [Tyr1162/1163]-phosphorylated IRβ, suggesting normal IR content and activation in the brains of nondiabetic sporadic AD cases. Moreover, total IRβ and [Tyr1162/1163]-phosphorylated IRβ levels in the hippocampal formation are not correlated with the severity of amyloid or tau-neuropathology. Exploring the regulation of glycogen synthase kinase 3 (GSK3) α/β, key IR-signaling components, we observed significantly lower levels of total GSK3 α/β in brain specimens from nondiabetic AD cases, suggesting that impaired IR signaling mechanisms might contribute to the onset and/or progression of AD dementia. Outcomes from our study support the development of insulin-sensitizing therapeutic strategies to stimulate downstream IR signaling in nondiabetic AD cases.
Highlights
Evidence from numerous epidemiological studies indicates that type 2 diabetes (T2D, a noninsulin-dependent form of diabetes mellitus) is associated with a two- to three-fold increase in the relative risk for Alzheimer’s disease (AD), independent of the risk for vascular dementia [1,2,3,4,5,6,7,8,9]
We investigated the contents of the insulin receptor-beta subunit (IRβ) and [Tyr1162/1163]-phosphorylated IRβ as surrogate indices of total IR content and IR activation in postmortem hippocampal formation brain specimens from nondiabetic sporadic Alzheimer’s disease (AD) cases
Consistent with our observation that AD-dementia in nondiabetic cases is not associated with significant changes in the contents of total IRβ or [Tyr1162/1163]-phosphorylated IRβ in the brain (Figures 2(c)-2(d)), we found that total or [Tyr1162/1163]-phosphorylated IRβ contents are not correlated with AD-type amyloid neuritic plaque (NP) or neurofibrillary tangle (NFT) neuropathology in the brain (Figures 4(a)–4(d))
Summary
Evidence from numerous epidemiological studies indicates that type 2 diabetes (T2D, a noninsulin-dependent form of diabetes mellitus) is associated with a two- to three-fold increase in the relative risk for Alzheimer’s disease (AD), independent of the risk for vascular dementia [1,2,3,4,5,6,7,8,9]. In addition to the direct roles of insulin and IDE, accumulating evidence shows that under diabetic conditions, impairments in certain insulin receptor- (IR-) responsive cellular signaling pathways might mechanistically promote AD-related neuropathology and cognitive deterioration [13,14,15,16,17,18]. Building on this observation, a recent hypothesis implicates impaired insulin signaling in the brain as a common underlying cause of sporadic AD, regardless of diabetic or nondiabetic status [19]
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