Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Jul 30;21(1):185.
doi: 10.1186/s12974-024-03184-7.

Differential effect of an evolving amyloid and tau pathology on brain phospholipids and bioactive lipid mediators in rat models of Alzheimer-like pathology

Sonia Do Carmo  1 , Marie-Audrey I Kautzmann  2 , Surjyadipta Bhattacharjee  2 , Bokkyoo Jun  2 , Carolyn Steinberg  3 , Joshua T Emmerson  3 , Janice C Malcolm  4 , Quentin Bonomo  5 , Nicolas G Bazan  6   7 , A Claudio Cuello  8   9   10   11
Affiliations

Differential effect of an evolving amyloid and tau pathology on brain phospholipids and bioactive lipid mediators in rat models of Alzheimer-like pathology

Sonia Do Carmo et al. J Neuroinflammation. .

Abstract

Background: Brain inflammation contributes significantly to the pathophysiology of Alzheimer's disease, and it is manifested by glial cell activation, increased production of cytokines/chemokines, and a shift in lipid mediators from a pro-homeostatic to a pro-inflammatory profile. However, whether the production of bioactive lipid mediators is affected at earlier stages, prior to the deposition of Aβ plaques and tau hyperphosphorylation, is unknown. The differential contribution of an evolving amyloid and tau pathology on the composition and abundance of membrane phospholipids and bioactive lipid mediators also remains unresolved.

Methods: In this study, we examined the cortical levels of DHA- and AA-derived bioactive lipid mediators and of membrane phospholipids by liquid chromatography with tandem mass spectrometry in transgenic rat models of the Alzheimer's-like amyloid and tau pathologies at early and advanced pathological stages.

Results: Our findings revealed a complex balance between pro-inflammatory and pro-resolving processes in which tau pathology has a more pronounced effect compared to amyloid pathology. At stages preceding tau misfolding and aggregation, there was an increase in pro-resolving lipid mediators (RVD6 and NPD1), DHA-containing phospholipids and IFN-γ levels. However, in advanced tau pathology displaying NFT-like inclusions, neuronal death, glial activation and cognitive deficits, there was an increase in cytokine and PGD2, PGE2, and PGF2α generation accompanied by a drop in IFN-γ levels. This pathology also resulted in a marked increase in AA-containing phospholipids. In comparison, pre-plaque amyloid pathology already presented high levels of cytokines and AA-containing phospholipids together with elevated RVD6 and NPD1 levels. Finally, Aβ plaque deposition was accompanied by a modest increase in prostaglandins, increased AA-containing phospholipids and reduced DHA-containing phospholipids.

Conclusions: Our findings suggest a dynamic trajectory of inflammatory and lipid mediators in the evolving amyloid and tau pathologies and support their differing roles on membrane properties and, consequentially, on signal transduction.

Keywords: Alzheimer’s disease; Amyloid pathology; Bioactive lipid mediators; Brain phospholipids; Lipidomics; Neuroinflammation; Tauopathy; Transgenic rat.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Schematic representation of the evolution of the amyloid and tau pathologies in the 3 lines of transgenic rats applied in this study. Note the accelerated tau pathology in R962- compared to the R955-hTau line. The time-points studied are indicated with red arrows in McGill-APP+/+ rats (6 and 16 months) and with red font in hTau rats (10 and 20 months)
Fig. 2
Fig. 2
Transgenic models expressing mutant human APP and MAPT exhibit progressive neuropathology. A. In 6-month-old McGill-R-Thy1-APP transgenic rats, human Aβ (McSA1) immunoreactivity is restricted to the intraneuronal compartment (left). By 16 months of age, human Aβ immunoreactivity has transitioned to the extracellular compartment and extensive Aβ plaque pathology is present (right). B. Levels of TBS-soluble and insoluble (formic-acid soluble) Aβ42 peptides were measured by ECLIA. C-D Both McGill-R955-hTau (C) and McGill-R962-hTau (D) transgenic rats display progressive tauopathy as assessed by HT-7 immunoreactivity. Note the hippocampal shrinkage and ventricular dilation in 20-month-old R962-hTau rats (right). Scale bar = 1000 μm. E-F. Levels of total tau (applying the pan-species antibody Tau5) and levels of NfL were assessed by Western blot analysis of cortical homogenates. (F) Quantification of the intensity of Tau5 and NfL immunoreactive bands. Values are expressed as means ± SEM (n = 4–5/group). Two-group comparisons were performed with the Mann-Whitney U test. Kruskal-Wallis with Dunn’s post hoc tests was used for multiple comparisons. # p < 0.05, ## p < 0.01 compared to age-matched wt rats; * p < 0.05, ** p < 0.01 compared to other groups
Fig. 3
Fig. 3
Cortical production of cytokines and chemokines in progressive amyloid and tau pathologies. Cortical production of IL-1β, IL-4, IL-6, IL-10, TNFα, KC/GRO and IFNγ were measured by ECLIA in McGill-R-hTau rats (A) and in McGill-R-Thy1-APP rats (B). Values are expressed as means ± SEM (n = 4–5/group). Two-group comparisons were performed with the Mann-Whitney U test. Kruskal-Wallis with Dunn’s post hoc tests was used for multiple comparisons. # p < 0.05 compared to age-matched wt rats. * p < 0.05 compared to other groups
Fig. 4
Fig. 4
Arachidonic acid-derived prostaglandins are highly increased at advanced stages of tau pathology. A. Arachidonic acid metabolism and production of eicosanoid lipid mediators including prostaglandins, leukotrienes and hydroxyeicosatetraenoic acids (HETEs). B-C. Levels of PGD2, PGE2, PGF2α in McGill-R-hTau rats (B) and in McGill-R-Thy1-APP rats (C). Two-group comparisons were performed with the Mann-Whitney U test. Kruskal-Wallis with Dunn’s post hoc tests was used for multiple comparisons. # p < 0.05 compared to age-matched wt rats. * p < 0.05, ** p < 0.01,*** p < 0.001 compared to other groups. D. Levels of prostaglandins and NfL are inversely correlated as assessed by Spearman’s correlation test
Fig. 5
Fig. 5
Docosahexaenoic acid-derived bioactive lipid mediators are affected by amyloid and tau pathology. A. Docosahexaenoic acid metabolism and production of DHA-derived pro-resolving lipid mediators including Resolvin RVD6, protectin (NPD1) and polyunsaturated fatty acids. B-C. Levels of RVD6 isoforms and NPD1 in McGill-hTau rats (B) and in McGill-APP rats (C). Two-group comparisons were performed with the Mann-Whitney U test. Kruskal-Wallis with Dunn’s post hoc tests was used for multiple comparisons. # p < 0.05, ### p < 0.001 compared to age-matched wt rats. * p < 0.05 compared to other groups. D. Levels of RVD6_8.29, RVD6_8.46, and RVD6_8.65 are directly correlated with NfL in McGill-hTau rats as assessed by a Spearman’s correlation test
Fig. 6
Fig. 6
Abundance of free very long-chain (> C24) polyunsaturated fatty acids (VLC-PUFA) is heightened in early-stage tau pathology. A. Levels of FA24:6, FA26:6, FA32:6, FA34:6 are increased in 10-month-old McGill-R955-hTau rats but not at an older age nor in McGill-R962-hTau rats. Levels of these PUFAs are not affected by amyloid pathology (B). Two-group comparisons were performed with the Mann-Whitney U test. Kruskal-Wallis with Dunn’s post hoc tests was used for multiple comparisons. # p < 0.05 compared to age-matched wt rats. * p < 0.05 compared to other groups
Fig. 7
Fig. 7
Altered abundance of DHA- and AA-containing phospholipids in response to amyloid and tau pathology. A. Heat map analysis of PCs, PEs, PSs, and SMs of 10- and 20-month-old McGill-R955-hTau, McGill-R962-hTau and age-matched wt rats (left) and of 6- and 16-month-old McGill-R-Thy1-APP and age-matched wt rats (right). Rows represent mean values of phospholipids and columns represent different ages and genotypes as indicated. B-C. Scatter plots of selected DHA- and AA-containing phospholipids show a decrease in DHA-containing phospholipids and an increase in AA-containing phospholipids in both APP and hTau rats. Two-group comparisons were performed with the Mann-Whitney U test. Kruskal-Wallis with Dunn’s post hoc tests was used for multiple comparisons. # p < 0.05, ### p < 0.001 compared to age-matched wt rats. * p < 0.05, ** p < 0.01 compared to other groups
Fig. 8
Fig. 8
Summary of the changes observed in this study. A. Changes in R955-hTau and R962-hTau rats. B. Changes in McGill-APP rats
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Jack CR Jr., Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, et al. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol. 2010;9:119–28. 10.1016/S1474-4422(09)70299-6 - DOI - PMC - PubMed
    1. Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet. 2009;41:1088–93. 10.1038/ng.440 - DOI - PMC - PubMed
    1. Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat Genet. 2009;41:1094–9. 10.1038/ng.439 - DOI - PubMed
    1. Holloway OG, Canty AJ, King AE, Ziebell JM. Rod microglia and their role in neurological diseases. Semin Cell Dev Biol. 2019;94:96–103. 10.1016/j.semcdb.2019.02.005 - DOI - PubMed
    1. Brouwers N, Van Cauwenberghe C, Engelborghs S, Lambert JC, Bettens K, Le Bastard N, et al. Alzheimer risk associated with a copy number variation in the complement receptor 1 increasing C3b/C4b binding sites. Mol Psychiatry. 2012;17:223–33. 10.1038/mp.2011.24 - DOI - PMC - PubMed

LinkOut - more resources