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. Key Words

This study was funded by the Seventh Framework Program of the European Commission (Grant No. 278486 [DEVELAGE project] to Isidre Ferrer and Andrea Fuso) and by the Spanish Ministry of Health, Instituto Carlos III (Fondo de Investigacio´n Sanitaria [FIS] PI1100968, FIS PI14/00757, and CIBERNED project BESAD-P to Isidre Ferrer; FIS PI 11/1532 to Manuel Portero-Otin; and Spanish Ministry of Economy and Competitiveness Grant Nos. BFU2009-11879/BFI and PI1300584 to Reinald Pamplona). Agatha Schlu¨ter was supported by FIS ECA07/055.