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01.12.2017 | Research article | Ausgabe 1/2017 Open Access

Molecular Neurodegeneration 1/2017

Decreased cortical FADD protein is associated with clinical dementia and cognitive decline in an elderly community sample

Zeitschrift:
Molecular Neurodegeneration > Ausgabe 1/2017
Autoren:
Alfredo Ramos-Miguel, Jesús A. García-Sevilla, Alasdair M. Barr, Thomas A. Bayer, Peter Falkai, Sue E. Leurgans, Julie A. Schneider, David A. Bennett, William G. Honer, M. Julia García-Fuster
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​s13024-017-0168-x) contains supplementary material, which is available to authorized users.

Abstract

Background

FADD (Fas-associated death domain) adaptor is a crucial protein involved in the induction of cell death but also mediates non-apoptotic actions via a phosphorylated form (p-Ser194-FADD). This study investigated the possible association of FADD forms with age-related neuropathologies, cognitive function, and the odds of dementia in an elderly community sample.

Methods

FADD forms were quantified by western blot analysis in dorsolateral prefrontal cortex (DLPFC) samples from a large cohort of participants in a community-based aging study (Memory and Aging Project, MAP), experiencing no-(NCI, n = 51) or mild-(MCI, n = 42) cognitive impairment, or dementia (n = 57).

Results

Cortical FADD was lower in subjects with dementia and lower FADD was associated with a greater load of amyloid-β pathology, fewer presynaptic terminal markers, poorer cognitive function and increased odds of dementia. Together with the observations of FADD redistribution into tangles and dystrophic neurites within plaques in Alzheimer’s disease brains, and its reduction in APP23 mouse cortex, the results suggest this multifunctional protein might participate in the mechanisms linking amyloid and tau pathologies during the course of the illness.

Conclusions

The present data suggests FADD as a putative biomarker for pathological processes associated with the course of clinical dementia.
Zusatzmaterial
Additional file 1: Figure S1. Colocalization of FADD and HLA-DR positive (activated) microglia in the DLPFC of neuropathology-free NCI (n = 3) MAP participants. Single-channel (in greys) or merged confocal images correspond to double co-immunolabeled sections with antibodies against FADD (H181, Santa-Cruz, 1:50; magenta) and HLA-DR (clone CR3/43, Dako, 1:100; green). In merged image, colors were arbitrarily assigned to maximize overlap visualization. Overlap panel is an ImageJ-generated bitmap highlighting those pixels where significant colocalization over an unbiased threshold of intensities between the indicated channels was detected in pairwise colocalization analyses. Unlike its neuronal localization pattern, FADD seems absent from the microglial nuclei, and mayor colocalization between these markers appears in activated microglial processes (see yellow arrows). Possibly, FADD microglial inclusions might derive from post-apoptotic neurons. Scale bar: 20 μm. (PDF 292 kb)
13024_2017_168_MOESM1_ESM.pdf
Additional file 2: Figure S2. (a) Representative full gel immunoblots of FADD, p-FADD and ß-actin proteins in the DLPFC of MAP participants, with various participants and standard (ST) samples. The red square represents the portion selected for Fig. 3d. (b) Representative full gel immunoblots of FADD and ß-actin proteins in cortical homogenates from APP23 transgenic mice. The red square represents the portion selected for Fig. 5b. The apparent molecular masses of the various proteins were determined by calibrating the blots with prestained molecular weight markers as shown on the left-hand side. (PDF 2893 kb)
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