title: 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.
authors: New Jersey Institute for Successful Aging at University of Medicine and Dentistry of New Jersey (UMDNJ) - School of Osteopathic Medicine, Stratford, NJ, USA.
authors: Nimish K
authors: NK
authors: Acharya
authors: Eli C
authors: EC
authors: Levin
authors: Peter M
authors: PM
authors: Clifford
authors: Min
authors: M
authors: Han
authors: Ryan
authors: R
authors: Tourtellotte
authors: Dean
authors: D
authors: Chamberlain
authors: Michael
authors: M
authors: Pollaro
authors: Nicholas J
authors: NJ
authors: Coretti
authors: Mary C
authors: MC
authors: Kosciuk
authors: Eric P
authors: EP
authors: Nagele
authors: Cassandra
authors: C
authors: Demarshall
authors: Theresa
authors: T
authors: Freeman
authors: Yi
authors: Y
authors: Shi
authors: Chenbing
authors: C
authors: Guan
authors: Colin H
authors: CH
authors: Macphee
authors: Robert L
authors: RL
authors: Wilensky
authors: Robert G
authors: RG
authors: Nagele
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001547:Benzaldehydes / Q000494:pharmacology / Q000627:therapeutic use*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006937:Hypercholesterolemia / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010091:Oximes / Q000494:pharmacology / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013552:Swine; D016896:Treatment Outcome; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides
chemical_list: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D016229:Amyloid beta-Peptides; D001547:Benzaldehydes; D010091:Oximes; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C529040:darapladib; D001713:Biphenyl Compounds; D004048:Diethylamines; D011744:Pyrimidinones; D013440:Sulfides