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Emre C, Do KV, Jun B, et al. Age-related changes in brain phospholipids and bioactive lipids in the APP knock-in mouse model of Alzheimer's disease. Acta Neuropathol Commun. 2021;9(1):116doi: 10.1186/s40478-021-01216-4.
Emre, C., Do, K. V., Jun, B., Hjorth, E., Alcalde, S. G., Kautzmann, M. I., Gordon, W. C., Nilsson, P., Bazan, N. G., & Schultzberg, M. (2021). Age-related changes in brain phospholipids and bioactive lipids in the APP knock-in mouse model of Alzheimer's disease. Acta neuropathologica communications, 9(1), 116. https://doi.org/10.1186/s40478-021-01216-4
Emre, Ceren, et al. "Age-related changes in brain phospholipids and bioactive lipids in the APP knock-in mouse model of Alzheimer's disease." Acta neuropathologica communications vol. 9,1 (2021): 116. doi: https://doi.org/10.1186/s40478-021-01216-4
Emre C, Do KV, Jun B, Hjorth E, Alcalde SG, Kautzmann MI, Gordon WC, Nilsson P, Bazan NG, Schultzberg M. Age-related changes in brain phospholipids and bioactive lipids in the APP knock-in mouse model of Alzheimer's disease. Acta Neuropathol Commun. 2021 Jun 29;9(1):116. doi: 10.1186/s40478-021-01216-4. PMID: 34187579; PMCID: PMC8244172.
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Acta Neuropathol Commun. 2021 Jun 29;9(1):116. doi: 10.1186/s40478-021-01216-4.

Age-related changes in brain phospholipids and bioactive lipids in the APP knock-in mouse model of Alzheimer's disease.

Acta neuropathologica communications

Ceren Emre, Khanh V Do, Bokkyoo Jun, Erik Hjorth, Silvia Gómez Alcalde, Marie-Audrey I Kautzmann, William C Gordon, Per Nilsson, Nicolas G Bazan, Marianne Schultzberg

Affiliations

  1. Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Center for Alzheimer Research, Karolinska Institutet, Stockholm, Sweden.
  2. Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health New Orleans, 2020 Gravier Street, Suite D, New Orleans, LA, 70112, USA.
  3. Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Center for Alzheimer Research, Karolinska Institutet, Stockholm, Sweden. [email protected].

PMID: 34187579 PMCID: PMC8244172 DOI: 10.1186/s40478-021-01216-4

Abstract

Sustained brain chronic inflammation in Alzheimer's disease (AD) includes glial cell activation, an increase in cytokines and chemokines, and lipid mediators (LMs), concomitant with decreased pro-homeostatic mediators. The inflammatory response at the onset of pathology engages activation of pro-resolving, pro-homeostatic LMs followed by a gradual decrease. We used an APP knock-in (App KI) AD mouse that accumulates β-amyloid (Aβ) and presents cognitive deficits (at 2 and 6 months of age, respectively) to investigate LMs, their precursors, biosynthetic enzymes and receptors, glial activation, and inflammatory proteins in the cerebral cortex and hippocampus at 2-, 4-, 8- and 18-month-old in comparison with wild-type (WT) mice. We used LC-mass-spectrometry and MALDI molecular imaging to analyze LMs and phospholipids, and immunochemistry for proteins. Our results revealed an age-specific lipid and cytokine profile, and glial activation in the App KI mice. Despite an early onset of Aβ pathology, pro-inflammatory and pro-resolving LMs were prominently increased only in the oldest age group. Furthermore, the LM biosynthetic enzymes increased, and their receptor expression decreased in the aged App KI mice. Arachidonic acid (AA)-containing phospholipid molecular species were elevated, correlating with decreased cPLA2 activity. MALDI molecular imaging depicted differential distribution of phospholipids according to genotype in hippocampal layers. Brain histology disclosed increased microglia proliferation starting from young age in the App KI mice, while astrocyte numbers were enhanced in older ages. Our results demonstrate that the brain lipidome is modified preferentially during aging as compared to amyloid pathology in the model studied here. However, alterations in phospholipids signal early pathological changes in membrane composition.

Keywords: Alzheimer; Amyloid; Astrocyte; Inflammation; Lipid mediators; Microglia; Phospholipids; Resolution

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