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

Nimish 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

Research output: Contribution to journalArticlepeer-review

113 Scopus citations

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 (Aβ 42), 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.

Original languageEnglish (US)
Pages (from-to)179-198
Number of pages20
JournalJournal of Alzheimer's Disease
Volume35
Issue number1
DOIs
StatePublished - 2013
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General Neuroscience
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

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