HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Diabetes and hypercholesterolemia increase blood-brain barrier permeability and brain amyloid deposition: beneficial effects of the LpPLA2 inhibitor darapladib.

Abstract
Diabetes mellitus (DM) and hypercholesterolemia (HC) have emerged as major risk factors for Alzheimer's disease, highlighting the importance of vascular health to normal brain functioning. Our previous study showed that DM and HC favor the development of advanced coronary atherosclerosis in a porcine model, and that treatment with darapladib, an inhibitor of lipoprotein-associated phospholipase A2, blocks atherosclerosis progression and improves animal alertness and activity levels. In the present study, we examined the effects of DM and HC on the permeability of the blood-brain barrier (BBB) using immunoglobulin G (IgG) as a biomarker. DMHC increased BBB permeability and the leak of microvascular IgG into the brain interstitium, which was bound preferentially to pyramidal neurons in the cerebral cortex. We also examined the effects of DMHC on the brain deposition of amyloid peptide (Aβ42), a well-known pathological feature of Alzheimer's disease. Nearly all detectable Aβ42 was contained within cortical pyramidal neurons and DMHC increased the density of Aβ42-loaded neurons. Treatment of DMHC animals with darapladib reduced the amount of IgG-immunopositive material that leaked into the brain as well as the density of Aβ42-containing neurons. Overall, these results suggest that a prolonged state of DMHC may have chronic deleterious effects on the functional integrity of the BBB and that, in this DMHC pig model, darapladib reduces BBB permeability. Also, the preferential binding of IgG and coincident accumulation of Aβ42 in the same neurons suggests a mechanistic link between the leak of IgG through the BBB and intraneuronal deposition of Aβ42 in the brain.
AuthorsNimish K Acharya, Eli C Levin, Peter M Clifford, Min Han, Ryan Tourtellotte, Dean Chamberlain, Michael Pollaro, Nicholas J Coretti, Mary C Kosciuk, Eric P Nagele, Cassandra Demarshall, Theresa Freeman, Yi Shi, Chenbing Guan, Colin H Macphee, Robert L Wilensky, Robert G Nagele
JournalJournal of Alzheimer's disease : JAD (J Alzheimers Dis) Vol. 35 Issue 1 Pg. 179-98 ( 2013) ISSN: 1875-8908 [Electronic] Netherlands
PMID23388174 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Amyloid beta-Peptides
  • Benzaldehydes
  • Oximes
  • Peptide Fragments
  • amyloid beta-protein (1-42)
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase
  • darapladib
Topics
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase (antagonists & inhibitors, metabolism)
  • Amyloid beta-Peptides (metabolism)
  • Animals
  • Benzaldehydes (pharmacology, therapeutic use)
  • Blood-Brain Barrier (drug effects, metabolism)
  • Brain (drug effects, metabolism, pathology)
  • Capillary Permeability (drug effects, physiology)
  • Diabetes Mellitus (drug therapy, metabolism, pathology)
  • Hypercholesterolemia (drug therapy, metabolism, pathology)
  • Oximes (pharmacology, therapeutic use)
  • Peptide Fragments (metabolism)
  • Random Allocation
  • Rats
  • Rats, Sprague-Dawley
  • Swine
  • Treatment Outcome

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: