Resolution of inflammation in Alzheimer’s disease
Wang, Xiuzhe
2014-12-02
09.30
Hörsalen, Novum, Floor 4, Huddinge
Inst för neurobiologi, vårdvetenskap och samhälle / Dept of Neurobiology, Care Sciences and Society
Inflammation is associated with Alzheimer’s disease (AD), a neurodegenerative disorder with
no cure up to date. Ample evidence from studies within various disciplines support that
inflammation plays a role in AD. Resolution of inflammation is the end stage of
inflammation, where the detrimental effects of inflammation are terminated and tissue
healing is initiated. Cutting-edge research has demonstrated that resolution of inflammation is
controlled by specialized pro-resolving lipid mediators (SPMs). There is emerging evidence
for a role of SPMs in various diseases associated with inflammation. One of the SPMs,
neuroprotectin D1 (NPD1) was the first to be found in reduced levels in the brain of AD
patients. The aims of this thesis were to investigate the resolution status in AD, the
mechanisms therein, and the therapeutic potential.
In Paper I, we aimed to answer the fundamental question, whether and how the resolution
pathway is altered in AD patients. To this end, we analysed cerebrospinal fluid (CSF) and
postmortem samples from AD and non-AD patients. We found that in the CSF and
hippocampus of AD patients, the levels of one of the SPMs, lipoxin A4, LXA4 were lower
than that in non-AD groups. This was further confirmed by analysis of a smaller number of
hippocampal samples with liquid chromatography - tandem mass spectrometry (LC-MS-MS)
technique, which also revealed that another SPM, maresin 1 (MaR1) was reduced in AD
hippocampus. Furthermore, the CSF levels of LXA4, as well as resolvin D1 (RvD1), were
positively correlated to mini mental statement examination (MMSE) scores. The cellular
distribution of two SPM receptors, LXA4 receptor/formyl peptide receptor 2 (ALX/FPR2)
and chemerin receptor 23 (ChemR23) were also described in the human brain. We then
investigated if the abnormal resolution may play a role in the pathogenesis of AD. For this
purpose, in Paper II, we used a senescence-accelerated mouse model, SAMP8 mice, to study
the balance between inflammation and resolution during an abnormal aging progress, since
the primary risk of AD is aging. We found that inflammation in SAMP8 mice increased with
age, and was higher than that in age-matched control mice. However, the resolution markers
LXA4 and RvD1 remained unchanged upon age in SAMP8 mice, or equal to the levels in
control mice. Thus, SAMP8 mice appeared to have an unresponsive resolution during the
abnormal aging. We also found that enzymes involved in the synthesis of SPMs were
abnormally regulated during aging in SAMP8 mice, and that this was related to amyloid β
(Aβ) and tau pathology. In Paper III, we analysed materials from a double-blind,
randomized, placebo-controlled clinical trial, where n-3 fatty acids or placebo were orally
supplemented to AD patients for 6 months. Peripheral blood mononuclear cells (PBMCs)
were obtained before and after the trial, and incubated with Aβ ex vivo. We found that there
was reduced production of LXA4 and RvD1 by the Aβ-exposed PBMCs in the placebo group,
and that n-3 fatty acid supplementation prevented this reduction. There was a positive
correlation between altered levels of plasma transthyretin, and the SPMs released from the
PBMCs. Finally, in Paper IV, we investigated the therapeutic potential of a resolutionstimulating strategy. Using LC-MS-MS technique, we were able to study a broad range of
lipid mediators, and found that MaR1 is also reduced in the entorhinal cortex of AD patients.
MaR1, as well as LXA4, RvD1, and NPD1 showed direct neuroprotective effects against
staurosporine-induced cell death in vitro, and MaR1 specifically exerted phenotypemodulation effects on human microglial cells, and promoted the phagocytosis of Aβ.
In conclusion, we have demonstrated that the resolution pathway is altered in AD, and has a
relationship with disease development and pathology. Novel therapeutic strategies based on
stimulating resolution should be further investigated.