Alzheimer's disease abeta vaccine reduces central nervous system abeta levels in a non-human primate, the Caribbean vervet.
Amyloid beta (Abeta) protein immunotherapy lowers cerebral Abeta and improves cognition in mouse models of Alzheimer's disease (AD). Here we show that Caribbean vervet monkeys (Chlorocebus aethiops, SK) develop cerebral Abeta plaques with aging and that these deposits are associated with gliosis and neuritic dystrophy. Five aged vervets were immunized with Abeta peptide over 10 months. Plasma and cerebral spinal fluid (CSF) samples were collected periodically from the immunized vervets and five aged controls; one monkey per group expired during the study. By Day 42, immunized animals generated plasma Abeta antibodies that labeled Abeta plaques in human, AD transgenic mouse and vervet brains; bound Abeta1-7; and recognized monomeric and oligomeric Abeta but not full-length amyloid precursor protein nor its C-terminal fragments. Low anti-Abeta titers were detected in CSF. Abetax-40 levels were elevated approximately 2- to 5-fold in plasma and decreased up to 64% in CSF in immunized vervets. Insoluble Abetax-42 was decreased by 66% in brain homogenates of the four immunized animals compared to archival tissues from 13 age-matched control vervets. Abeta42-immunoreactive plaques were detected in frontal cortex in 11 of the 13 control animals, but not in six brain regions examined in each of the four immunized vervets. No T cell response or inflammation was observed. Our study is the first to demonstrate age-related Abeta deposition in the vervet monkey as well as the lowering of cerebral Abeta by Abeta vaccination in a non-human primate. The findings further support Abeta immunotherapy as a potential prevention and treatment of AD.
Lemere
Cynthia A
CA
Center for Neurologic Diseases, HIM 622, Department of Neurology, Brigham & Women's Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02215, USA. clemere@rics.bwh.harvard.edu
Beierschmitt
Amy
A
Iglesias
Melitza
M
Spooner
Edward T
ET
Bloom
Jeanne K
JK
Leverone
Jodi F
JF
Zheng
Jessica B
JB
Seabrook
Timothy J
TJ
Louard
Dora
D
Li
Diana
D
Selkoe
Dennis J
DJ
Palmour
Roberta M
RM
Ervin
Frank R
FR
D000367:Age Factors; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D023582:Alzheimer Vaccines / Q000008:administration & dosage*; D016229:Amyloid beta-Peptides / Q000008:administration & dosage*; D000818:Animals; D015153:Blotting, Western; D002490:Central Nervous System / Q000378:metabolism* / Q000473:pathology; D002522:Chlorocebus aethiops / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D019579:Neocortex / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000008:administration & dosage*; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D013997:Time Factors
D023582:Alzheimer Vaccines; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)