title: Neuroinflammatory signals in Alzheimer disease and APP/PS1 transgenic mice: correlations with plaques, tangles, and oligomeric species.
abstract: To understand neuroinflammation-related gene regulation during normal aging and in sporadic Alzheimer disease (sAD), we performed functional genomics analysis and analyzed messenger RNA (mRNA) expression by quantitative reverse transcription-polymerase chain reaction of 22 genes involved in neuroinflammation-like responses in the cerebral cortex of wild-type and APP/PS1 transgenic mice. For direct comparisons, mRNA expression of 18 of the same genes was then analyzed in the entorhinal cortex, orbitofrontal cortex, and frontal cortex area 8 of middle-aged human subjects lacking Alzheimer disease-related pathology and in older subjects with sAD pathology covering Stages I-II/0(A), III-IV/A-B, and V-VI/C of Braak and Braak classification. Modifications of cytokine and immune mediator mRNA expression were found with normal aging in wild-type mice and in middle-aged individuals and patients with early stages of sAD-related pathology; these were accompanied by increased protein expression of certain mediators in ramified microglia. In APP/PS1 mice, inflammatory changes coincided with β-amyloid (Aβ) deposition; increased levels of soluble oligomers paralleled the modified mRNA expression of cytokines and mediators in wild-type mice. In patients with sAD, regulation was stage- and region-dependent and not merely acceleration and exacerbation of mRNA regulation with aging. Gene regulation at first stages of AD was not related to hyperphosphorylated tau deposition in neurofibrillary tangles, Aβ plaque burden, concentration of Aβ1-40 (Aβ40) and Aβ1-42 (Aβ42), or fibrillar Aβ linked to membranes but rather to increased levels of soluble oligomers. Thus, species differences and region- and stage-dependent inflammatory responses in sAD, particularly at the initial stages, indicate the need to identify new anti-inflammatory compounds with specific molecular therapeutic targets.
authors.affiliation: From the Institut de Neuropatologia, Institut d'Investigació Biomèdica de Bellvitge-Hospital Universitari de Bellvitge (IL-G, EA, PG-E, BA, FL, MC, JM, AP, IF); Universitat de Barcelona (IF); and Neurometabolic Diseases Laboratory, Institut d'Investigació Biomèdica de Bellvitge (AS, AP), Hospitalet de Llobregat; Catalan Institution for Research and Advanced Studies (AP), Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (IF) and Center for Biomedical Research on Rare Diseases (AS, AP), Madrid; and Department of Experimental Medicine, University of Lleida-Biomedical Research Institute of Lleida, Lleida (MP-O, RP), Spain; and Section Neuroscience, Department of Psychology, Sapienza University of Rome (AF); and European Center for Brain Research/IRCCS Santa Lucia Foundation (AF), Rome, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: López-González
authors.forename: Agatha
authors.initials: A
authors.lastname: Schlüter
authors.forename: Ester
authors.initials: E
authors.lastname: Aso
authors.forename: Paula
authors.initials: P
authors.lastname: Garcia-Esparcia
authors.forename: Belen
authors.initials: B
authors.lastname: Ansoleaga
authors.forename: Franc
authors.initials: F
authors.lastname: LLorens
authors.forename: Margarita
authors.initials: M
authors.lastname: Carmona
authors.forename: Jesús
authors.initials: J
authors.lastname: Moreno
authors.forename: Andrea
authors.initials: A
authors.lastname: Fuso
authors.forename: Manuel
authors.initials: M
authors.lastname: Portero-Otin
authors.forename: Reinald
authors.initials: R
authors.lastname: Pamplona
authors.forename: Aurora
authors.initials: A
authors.lastname: Pujol
authors.forename: Isidre
authors.initials: I
authors.lastname: Ferrer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000096:biosynthesis*; D058225:Plaque, Amyloid / Q000378:metabolism* / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018836:Inflammation Mediators; D010446:Peptide Fragments; D053764:Presenilin-1; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)