Strategic delivery of Omega-3 fatty acids for modulating inflammatory neurodegenerative diseases

Objectives: Early-life inflammatory events like infections and injuries
may predispose the brain to Alzheimer's disease (AD) by disrupting
neurodevelopment and raising vulnerability. The association between early
neuroinflammation and subsequent neurodegeneration leading to dementia
remains unclear. We hypothesize that omega-3 (n-3) fatty acids (FA),
especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA),
positively regulate neuro-immune cells, preserving their cell membrane
structure and metabolic homeostasis. Our study examined whether strategic
delivery of n-3 FA via injectable n-3 triglycerides (TG) can influence
microglial lipid metabolism to prevent or delay AD progression. Methods
and results: We characterized n-3 treatment effects on modulating lipid
and metabolic homeostasis in microglia during the critical window of brain
development. Our preliminary studies on determining the effects of early
n-3 treatment on brain cell homeostasis indicate that perinatal bolus n-3
TG injections suppressed activation of gliosis-associated markers in young
mice predisposed to AD (5xFAD) and yielded sustained regulatory effects on
the expression of inflammatory molecules, such as interleukin-6 (Il6) and
tumor necrosis factor-alpha (Tnfa), in adult brains. A significant
increase in high-frequency ultrasonic vocalizations (USV) was observed in
P6 5xFAD mice that received perinatal n-3 compared to vehicle control,
implicating enhanced active communication patterns. Improvement in
behavior deficits was observed in n-3-treated adult AD mice. Perinatal n-3
TG treatment modified brain lipid composition in young offspring,
increasing key membrane lipid species, such as phospholipids (PL) and
lysophospholipids (lysoPL). Pro-inflammatory sphingolipids associated with
neurodegeneration, including lactosylceramide, were significantly lower in
mice treated with n-3 than those in saline-treated AD mice. Conclusions:
Our study establishes a proof of principle for targeting brain immune cell
metabolism with injectable n-3 TG to mitigate neuroinflammation in AD
pathogenesis, paving the way for future research into early treatments for
related central nervous system (CNS) disorders.