Nasal vaccination with a proteosome-based adjuvant and glatiramer acetate clears beta-amyloid in a mouse model of Alzheimer disease.
Amyloid beta-peptide (Abeta) appears to play a key pathogenic role in Alzheimer disease (AD). Immune therapy in mouse models of AD via Abeta immunization or passive administration of Abeta antibodies markedly reduces Abeta levels and reverses behavioral impairment. However, a human trial of Abeta immunization led to meningoencephalitis in some patients and was discontinued. Here we show that nasal vaccination with a proteosome-based adjuvant that is well tolerated in humans plus glatiramer acetate, an FDA-approved synthetic copolymer used to treat multiple sclerosis, potently decreases Abeta plaques in an AD mouse model. This effect did not require the presence of antibody, as it was observed in B cell-deficient (Ig mu-null) mice. Vaccinated animals developed activated microglia that colocalized with Abeta fibrils, and the extent of microglial activation correlated strongly with the decrease in Abeta fibrils. Activation of microglia and clearing of Abeta occurred with the adjuvant alone, although to a lesser degree. Our results identify a novel approach to immune therapy for AD that involves clearing of Abeta through the utilization of compounds that have been safely tested on or are currently in use in humans.
Frenkel
Dan
D
Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Maron
Ruth
R
Burt
David S
DS
Weiner
Howard L
HL
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000627:therapeutic use; D000281:Administration, Intranasal; D000544:Alzheimer Disease / Q000188:drug therapy / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000166:cytology; D001921:Brain / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D003546:Cysteine Endopeptidases / Q000008:administration & dosage / Q000627:therapeutic use; D004195:Disease Models, Animal; D004338:Drug Combinations; D005260:Female; D000068717:Glatiramer Acetate; D006801:Humans; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000627:therapeutic use*; D046988:Proteasome Endopeptidase Complex; D014611:Vaccination
D000276:Adjuvants, Immunologic; D016229:Amyloid beta-Peptides; D015703:Antigens, CD; D004338:Drug Combinations; D008070:Lipopolysaccharides; D010455:Peptides; C493785:Protollin; D000068717:Glatiramer Acetate; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex