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O5‐03‐02: GLYMPHATIC FLUID PHARMACOLOGY: FACILITATION OF B‐AMYLOID CLEARANCE
Author(s) -
Nakada Tsutomu,
Kwee Ingrid L.
Publication year - 2016
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2016.06.717
Subject(s) - in vivo , pharmacology , chemistry , aquaporin 1 , extracellular , neuroscience , biophysics , medicine , psychology , biochemistry , biology , water channel , mechanical engineering , microbiology and biotechnology , engineering , inlet
Background:APOE genotype is the foremost genetic risk factor for sporadic Alzheimer’s disease (AD) and influences the load of bamyloid (Ab) deposition in the brain. To investigate how APOE genotype modulates response to anti-Ab immunotherapy we administered 10D5 anti-Abmonoclonal antibody (mAb) to APPSW/PS1dE9 (APP) AD model mice with targeted replacement (TR) of the murine Apoe gene for various human APOE alleles. Methods:APP/ APOE-TR mice received 10D5 mAb or TY11-15 isotypal control IgG between the age of 12 and 15 months. In vivo mMRI was used to monitor Amyloid Related Imaging Abnormalities (ARIA) in APP/ε4 mice undergoing the treatment. Postmortem evaluation included assessment of parenchymal Ab plaque load, microglia response, vascular Ab deposition, and perivascular hemosiderin deposits reflecting ensued microhemorrhages. Results:Occurrence of new microhemorrhages (ARIA-H) was infrequently detected by mMRI in APP/ε4 mice undergoing 10D5 mAb treatment and we found no evidence of “vasogenic edema” (ARIA-E). Although relative reduction in the parenchymal Ab plaque load in response to 10D5 mAb immunization was comparable across all APOE genotypes, APP/ε4 mice showed the greatest reduction in the absolute values of Ab plaque load, given their highest baseline. 10D5 mAb promoted microglia activation, which in APP/ε4 mice was the most robust and out of proportion to the post-treatment Ab plaque load suggesting defective Ab phagocytosis associated with the ε4 allele. Perivascular hemosiderin deposits were associated with vascular Ab deposition and were ubiquitous in control mice of all APOE genotypes although in APP/ε3 mice their incidence was significantly lower than that in APP/ε2 and APP/ε4 mice. 10D5 mAb but not TY11-15 treatment effected significant reduction in the load of vascular Ab deposition but increased the occurrence of perivascular hemosiderin deposits across all APOE genotypes with the most robust and the weakest effects seen in APP/ε2 and APP/ε3 mice, respectively. Conclusions:APOE genotype differentially affect microglia activation and Ab plaque load reduction resulting from anti-Ab passive immunization. The APOE ε3 allele shows strong protective effect against vasculotropic complications of anti-Ab immunization, while conversely the APOE ε2 allele is associated with significantly increased risk of cerebral microhemorrhages.