title: 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 beta protein precursor (AbetaPP), 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.
authors.affiliation: Department of Pathology, Rhode Island Hospital and Brown Medical School, Providence, RI 02903, USA.
authors.forename: Enrique J
authors.initials: EJ
authors.lastname: Rivera
authors.forename: Alison
authors.initials: A
authors.lastname: Goldin
authors.forename: Noah
authors.initials: N
authors.lastname: Fulmer
authors.forename: Rose
authors.initials: R
authors.lastname: Tavares
authors.forename: Jack R
authors.initials: JR
authors.lastname: Wands
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: de la Monte
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000502:physiology; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology*; D002795:Choline O-Acetyltransferase / Q000235:genetics; D003072:Cognition Disorders / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D005838:Genotype; D005947:Glucose / Q000627:therapeutic use; D006801:Humans; D007328:Insulin / Q000235:genetics*; D007333:Insulin Resistance / Q000502:physiology; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; D017931:DNA Primers; D007328:Insulin; D012333:RNA, Messenger; D016875:tau Proteins; D007334:Insulin-Like Growth Factor I; D002795:Choline O-Acetyltransferase; D005947:Glucose; D000109:Acetylcholine