Age-related changes in brain phospholipids and bioactive lipids in the APP knock-in mouse model of Alzheimer's disease.
Ceren EmreKhanh V DoBokkyoo JunErik HjorthSilvia Gómez AlcaldeMarie-Audrey I KautzmannWilliam C GordonPer NilssonNicolas G BazanMarianne SchultzbergPublished in: Acta neuropathologica communications (2021)
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.
Keyphrases
- mass spectrometry
- wild type
- fatty acid
- early onset
- cerebral ischemia
- inflammatory response
- resting state
- high fat diet induced
- white matter
- functional connectivity
- mouse model
- neuropathic pain
- anti inflammatory
- neoadjuvant chemotherapy
- liquid chromatography
- oxidative stress
- single cell
- physical activity
- high resolution
- insulin resistance
- multiple sclerosis
- signaling pathway
- squamous cell carcinoma
- stem cells
- mesenchymal stem cells
- blood brain barrier
- lipopolysaccharide induced
- gas chromatography
- brain injury
- cell therapy
- metabolic syndrome
- skeletal muscle
- radiation therapy
- middle aged
- locally advanced
- lps induced
- rectal cancer