Vaccination of Alzheimer's model mice with Abeta derivative in alum adjuvant reduces Abeta burden without microhemorrhages.
Immunotherapy holds great promise for Alzheimer's disease (AD) and other conformational disorders but certain adverse reactions need to be overcome. The meningoencephalitis observed in the first AD vaccination trial was likely related to excessive cell-mediated immunity caused by the immunogen, amyloid-beta (Abeta) 1-42, and the adjuvant, QS-21. To avoid this toxicity, we have been using Abeta derivatives in alum adjuvant that promotes humoral immunity. Other potential side effects of immunotherapy are increased vascular amyloid and associated microhemorrhages that may be related to rapid clearance of parenchymal amyloid. Here, we determined if our immunization strategy was associated with this form of toxicity, and if the therapeutic effect was age-dependent. Tg2576 mice and wild-type littermates were immunized from 11 or 19 months and their behaviour evaluated prior to killing at 24 months. Subsequently, plaque- and vascular-Abeta burden, Abeta levels and associated pathology was assessed. The therapy started at the cusp of amyloidosis reduced cortical Abeta deposit burden by 31% and Abeta levels by 30-37%, which was associated with cognitive improvements. In contrast, treatment from 19 months, when pathology is well established, was not immunogenic and therefore did not reduce Abeta burden or improve cognition. Significantly, the immunotherapy in the 11-24 months treatment group, that reduced Abeta burden, did not increase cerebral bleeding or vascular Abeta deposits in contrast to several Abeta antibody studies. These findings indicate that our approach age-dependently improves cognition and reduces Abeta burden when used with an adjuvant suitable for humans, without increasing vascular Abeta deposits or microhemorrhages.
Asuni
Ayodeji A
AA
Department of Psychiatry, New York University School of Medicine, Millhauser Laboratories, 560 First Avenue, New York, NY 10016, USA.
Boutajangout
Allal
A
Scholtzova
Henrieta
H
Knudsen
Elin
E
Li
Yong Sheng
YS
Quartermain
David
D
Frangione
Blas
B
Wisniewski
Thomas
T
Sigurdsson
Einar M
EM
D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000367:Age Factors; D000534:Alum Compounds / Q000008:administration & dosage; D000544:Alzheimer Disease / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D023582:Alzheimer Vaccines / Q000627:therapeutic use; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000276:immunology / Q000627:therapeutic use*; D000818:Animals; D001921:Brain / Q000276:immunology / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000209:etiology*; D003071:Cognition; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008297:Male; D018782:Maze Learning; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity; D010446:Peptide Fragments / Q000276:immunology / Q000627:therapeutic use; D058225:Plaque, Amyloid / Q000473:pathology; D013997:Time Factors; D014611:Vaccination / Q000379:methods*
D000276:Adjuvants, Immunologic; D000534:Alum Compounds; D023582:Alzheimer Vaccines; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments