Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer's disease: Link to brain reductions in acetylcholine

Abstract

Reduced glucose utilization and energy metabolism occur early in the course of Alzheimer's disease (AD) and correlate with impaired cognition. Glucose utilization and energy metabolism are regulated by insulin and insulin-like growth factor I (IGF-I), and correspondingly, studies have shown that cognitive impairment may be improved by glucose or insulin administration. Recently, we demonstrated significantly reduced levels of insulin and IGF-I polypeptide genes and their corresponding receptors in advanced AD relative to aged control brains. The abnormalities in gene expression were accompanied by impaired survival signaling downstream through PI3 kinase-Akt. The present work characterizes the abnormalities in insulin and IGF gene expression and receptor binding in brains with different Braak stage severities of AD. Realtime quantitative RT-PCR analysis of frontal lobe tissue demonstrated that increasing AD Braak Stage was associated with progressively reduced levels of mRNA corresponding to insulin, IGF-I, and IGF-II polypeptides and their receptors, tau, which is regulated by insulin and IGF-I, and the Hu D neuronal RNA binding protein. In contrast, progressively increased levels of amyloid β protein precursor (AβPP), glial fibrillary acidic protein, and the IBA1/AIF1 microglial mRNA transcripts were detected with increasing AD Braak Stage. Impairments in growth factor and growth factor receptor expression and function were associated with increasing AD Braak stage dependent reductions in insulin, IGF-I, and IGF-II receptor binding, ATP levels, and choline acetyltransferase (ChAT) expression. Further studies demonstrated that: 1) ChAT expression increases with insulin or IGF-I stimulation; 2) ChAT is expressed in insulin and IGF-I receptor-positive cortical neurons; and 3) ChAT co-localization in insulin or IGF-I receptor-positive neurons is reduced in AD. Together, these data provide further evidence that AD represents a neuro-endocrine disorder that resembles a unique form of diabetes mellitus (? Type 3) and progresses with severity of neurodegeneration.

Glatiramer acetate fights against Alzheimer’s disease by inducing dendritic-like microglia expressing insulin-like growth factor 1

“…The vaccinated mice in this study demonstrated reduced cognitive loss and increased neurogenesis relative to untreated Tg-AD mice. These two aspects of hippocampal plasticity are apparently related to the presence of IGF1 (9,11,(34)(35)(36). Reported observations in Tg-AD mice housed in an enriched environment also support a link between mechanisms associated with neurogenesis (23) and with plaque reduction (37).…”

Aging and Alzheimer’s disease: Comparison and associations from molecular to system level

“…Clinically, there is a higher density of insulin receptors in the brain of patients with AD compared to control subjects, possibly reflecting upregulation of the receptor in an attempt to compensate for the decreased functionality of insulin (Frolich et al, 1998). By contrast, some studies reported decreased insulin receptor binding in individuals with AD in comparison with age‐matched control (Arnold et al, 2018; Rivera et al, 2005; Steen et al, 2005). For example, reduced insulin, insulin receptor, IGF1 and IGF2, reduced total IRS1 mRNA expression, and reduced protein indicators of downstream insulin signaling activity (including p85‐associated IRS1, phosphorylated AKT) have been reported in postmortem AD brain (Steen et al, 2005).…”

Insulin resistance, dyslipidemia, and apolipoprotein E interactions as mechanisms in cognitive impairment and Alzheimer's disease

“…38,39 There have been many post-mortem brain studies showing decreases in key insulin signaling proteins in the brains of people with AD. [40][41][42][43] In addition, Talbot et al 44 showed an impaired response to insulin in post-mortem brain regions including the cerebellar cortex and hippocampal formation compared to healthy controls who did not have evidence of insulin resistance at peripheral tissues. 44 This study was critical to show a functional impairment in response to insulin in the CNS, but not necessarily the peripheral tissues, in people with cognitive impairment.…”