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. 2013 Apr;34(4):1051-9.
doi: 10.1016/j.neurobiolaging.2012.09.012. Epub 2012 Oct 9.

Neuroinflammatory phenotype in early Alzheimer's disease

Tiffany L Sudduth  1 , Frederick A Schmitt, Peter T Nelson, Donna M Wilcock
Affiliations

Neuroinflammatory phenotype in early Alzheimer's disease

Tiffany L Sudduth et al. Neurobiol Aging. 2013 Apr.

Abstract

Alzheimer's disease (AD) involves progressive neurodegeneration in the presence of misfolded proteins and poorly-understood inflammatory changes. However, research has shown that AD is genetically, clinically, and pathologically heterogeneous. In frozen brain samples of frontal cortex (diseased) and cerebellum (nondiseased) from the University of Kentucky Alzheimer's Disease Center autopsy cohort, we performed gene expression analysis for genes categorizing inflammatory states (termed M1 and M2) from early and late stage AD, and age-matched nondemented controls. We performed analysis of the serum samples for a profile of inflammatory proteins and examined the neuropathologic data on these samples. Striking heterogeneity was found in early AD. Specifically, early-stage AD brain samples indicated apparent polarization toward either the M1 or M2 brain inflammatory states when compared with age-matched nondisease control tissue. This polarization was observed in the frontal cortex and not in cerebellar tissue. We were able to detect differences in AD neuropathology, and changes in serum proteins that distinguished the individuals with apparent M1 versus M2 brain inflammatory polarization.

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Figures

Figure 1
Figure 1
Early-stage AD brain neuroinflammatory gene expression shows separation into two clusters. Panel A shows the genes that have been measured in the current study. Panel B shows the K-means cluster analysis for the M1 and M2a neuroinflammatory markers that showed significant differences. Panel C shows the cluster means highlighting the pattern of relative gene expression in our two clusters.
Figure 2
Figure 2
Early-stage AD brain shows a heterogeneous inflammatory response with polarization to the M1 or M2a neuroinflammatory states while the late-stage AD brain does not. Panels A-F show relative gene expression for early-stage AD (A-D) or late-stage AD (E-F) frontal cortex (A-B and E) and cerebellum (C-D and F). The dashed line on each graph represents the mean expression of the age-matched, non-demented controls. * indicates P<0.05, ** indicates P<0.01.
Figure 3
Figure 3
Early-stage AD neuropathology and amyloid load is different between the M1 and M2a neuroinflammatory polarized samples. Panels A-D show Aβ staining in the frontal cortex of M1 polarized samples (A-B) and M2a polarized samples (C-D). Mag = 100X. E shows numbers of diffuse and neuritic plaques and tangles in the frontal cortex. F and G show soluble (F) and insoluble (G) Aβ levels measured by ELISA. ** indicates P<0.01.
Figure 4
Figure 4
Cerebrovascular disease is more prevalent in the M2a neuroinflammatory polarized samples than the M1 polarized samples. Panel A shows the cerebrovascular risk factors assessed. Panel B shows the mean number of risk factors per patient. Panel G shows CAA prevalence and Aβ40:Aβ42 ratios for each inflammatory group. ** indicates P<0.01.
Figure 5
Figure 5
Several serum proteins can be used to distinguish M1 polarization from M2a polarization. Serum was analyzed for 46 inflammation associated proteins listed in panel A. Panel B shows those proteins that were significantly different between M1 and M2a polarized early-stage AD samples. * indicates P<0.05, ** indicates P<0.01.
See this image and copyright information in PMC

References

    1. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, Finch CE, Frautschy S, Griffin WS, Hampel H, Hull M, Landreth G, Lue L, Mrak R, Mackenzie IR, McGeer PL, O’Banion MK, Pachter J, Pasinetti G, Plata-Salaman C, Rogers J, Rydel R, Shen Y, Streit W, Strohmeyer R, Tooyoma I, Van Muiswinkel FL, Veerhuis R, Walker D, Webster S, Wegrzyniak B, Wenk G, Wyss-Coray T. Inflammation and Alzheimer’s disease. Neurobiology of aging. 2000;21(3):383–421. - PMC - PubMed
    1. Bowler JV, Munoz DG, Merskey H, Hachinski V. Fallacies in the pathological confirmation of the diagnosis of Alzheimer’s disease. Journal of neurology, neurosurgery, and psychiatry. 1998;64(1):18–24. - PMC - PubMed
    1. Breitner JC, Baker LD, Montine TJ, Meinert CL, Lyketsos CG, Ashe KH, Brandt J, Craft S, Evans DE, Green RC, Ismail MS, Martin BK, Mullan MJ, Sabbagh M, Tariot PN. Extended results of the Alzheimer’s disease anti-inflammatory prevention trial. Alzheimer’s & dementia : the journal of the Alzheimer’s Association. 2011;7(4):402–11. doi:10.1016/j.jalz.2010.12.014. - PMC - PubMed
    1. Breitner JC, Haneuse SJ, Walker R, Dublin S, Crane PK, Gray SL, Larson EB. Risk of dementia and AD with prior exposure to NSAIDs in an elderly community-based cohort. Neurology. 2009;72(22):1899–905. doi:10.1212/WNL.0b013e3181a18691. - PMC - PubMed
    1. Breitner JC, Martin BK, Meinert CL. The suspension of treatments in ADAPT: concerns beyond the cardiovascular safety of celecoxib or naproxen. PLoS clinical trials. 2006;1(8):e41. doi:10.1371/journal.pctr.0010041. - PMC - PubMed

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