Brain region–specific lipid alterations in the PLB4 hBACE1 knock-in mouse model of Alzheimer’s disease

Madhurima Dey, Frank J Gunn-Moore, Bettina Platt, Terry K Smith* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Background
Lipid dysregulation is associated with several key characteristics of Alzheimer’s disease (AD), including amyloid-β and tau neuropathology, neurodegeneration, glucose hypometabolism, as well as synaptic and mitochondrial dysfunction. The β-site amyloid precursor protein cleavage enzyme 1 (BACE1) is associated with increased amyloidogenesis, and has been affiliated with diabetes via its role in metabolic regulation.

Methods
The research presented herein investigates the role of hBACE1 in lipid metabolism and whether specific brain regions show increased vulnerability to lipid dysregulation. By utilising advanced mass spectrometry techniques, a comprehensive, quantitative lipidomics analysis was performed to investigate the phospholipid, sterol, and fatty acid profiles of the brain from the well-known PLB4 hBACE1 knock-in mouse model of AD, which also shows a diabetic phenotype, to provide insight into regional alterations in lipid metabolism.

Results
Results show extensive region – specific lipid alterations in the PLB4 brain compared to the wild-type, with decreases in the phosphatidylethanolamine content of the cortex and triacylglycerol content of the hippocampus and hypothalamus, but increases in the phosphatidylcholine, phosphatidylinositol, and diacylglycerol content of the hippocampus. Several sterol and fatty acids were also specifically decreased in the PLB4 hippocampus.

Conclusion
Collectively, the lipid alterations observed in the PLB4 hBACE1 knock-in AD mouse model highlights the regional vulnerability of the brain, in particular the hippocampus and hypothalamus, to lipid dysregulation, hence supports the premise that metabolic abnormalities have a central role in both AD and diabetes.

Original languageEnglish
Article number201
JournalLipids in Health & Disease
Volume19
DOIs
Publication statusPublished - 31 Aug 2020

Keywords

  • PLB4
  • quantitative lipidomics
  • brain regions
  • Brain regions
  • Quantitative lipidomics
  • WHITE-MATTER
  • CHOLESTEROL
  • AMYLOID-PRECURSOR-PROTEIN
  • FATTY-ACIDS
  • MECHANISMS
  • MILD COGNITIVE IMPAIRMENT
  • APOLIPOPROTEIN-E
  • PATHOPHYSIOLOGY
  • TARGETED LIPIDOMICS
  • DIACYLGLYCEROLS

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