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

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.

Modulation of Neurolipid Signaling and Specific Lipid Species in the Triple Transgenic Mouse Model of Alzheimer’s Disease

“…Moreover, the modulations of PC and PI species depend on their fatty acid composition, i.e., decrease of polyunsaturated fatty acid (PUFA) phospholipids and increase of phospholipid species containing saturated fatty acids (SFA). Similar results have been reported in serum and tissue of AD patients [31][32][33]35] and also in another AD transgenic mice model [97,99]. The decrease in phospholipids containing PUFA could be related to impairment of the cell membranes during AD pathogenesis.…”

Ursolic acid treats renal tubular epithelial cell damage induced by calcium oxalate monohydrate via inhibiting oxidative stress and inflammation

“…Immunohistochemical analysis was performed based on previous studies [ 17 ]. The sections were deparaffinized at 60°C for 1 h, washed twice in xylene for 10 min, and later rehydrated in descending alcohol series.…”

Specialized Pro-Resolving Mediators in Neuroinflammation: Overview of Studies and Perspectives of Clinical Applications

“…The finding that SPMs receptors are increased in the AD brain in post-mortem studies and correlate to Braak stages, suggests a prominent role of resolution pathways; the increase in these receptors may either represent a primary factor in the pathogenesis of the disease or a consequence of failed resolution [ 78 ]. The same study group investigated age-related changes in the LM profile in the APP knock-in (APP KI) mouse model of AD, concluding that the brain lipidome appeared to be modified preferentially during aging as compared to amyloid pathology, as the oldest age group was the one with the greatest increase in LMs, despite an early onset of Aβ pathology [ 79 ]. In this case, the SPMs biosynthetic enzymes were found to be increased, while their receptor expression decreased in the aged App KI mice, in disagreement with their previous work [ 78 ] on AD patients.…”