Epitope and isotype specificities of antibodies to beta -amyloid peptide for protection against Alzheimer's disease-like neuropathology.
Transgenic PDAPP mice, which express a disease-linked isoform of the human amyloid precursor protein, exhibit CNS pathology that is similar to Alzheimer's disease. In an age-dependent fashion, the mice develop plaques containing beta-amyloid peptide (Abeta) and exhibit neuronal dystrophy and synaptic loss. It has been shown in previous studies that pathology can be prevented and even reversed by immunization of the mice with the Abeta peptide. Similar protection could be achieved by passive administration of some but not all monoclonal antibodies against Abeta. In the current studies we sought to define the optimal antibody response for reducing neuropathology. Immune sera with reactivity against different Abeta epitopes and monoclonal antibodies with different isotypes were examined for efficacy both ex vivo and in vivo. The studies showed that: (i) of the purified or elicited antibodies tested, only antibodies against the N-terminal regions of Abeta were able to invoke plaque clearance; (ii) plaque binding correlated with a clearance response and neuronal protection, whereas the ability of antibodies to capture soluble Abeta was not necessarily correlated with efficacy; (iii) the isotype of the antibody dramatically influenced the degree of plaque clearance and neuronal protection; (iv) high affinity of the antibody for Fc receptors on microglial cells seemed more important than high affinity for Abeta itself; and (v) complement activation was not required for plaque clearance. These results indicate that antibody Fc-mediated plaque clearance is a highly efficient and effective process for protection against neuropathology in an animal model of Alzheimer's disease.
Bard
Frédérique
F
Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, CA 94080, USA. frederique.bard@elan.com
Barbour
Robin
R
Cannon
Catherine
C
Carretto
Robert
R
Fox
Michael
M
Games
Dora
D
Guido
Teresa
T
Hoenow
Kathleen
K
Hu
Kang
K
Johnson-Wood
Kelly
K
Khan
Karen
K
Kholodenko
Dora
D
Lee
Celeste
C
Lee
Mike
M
Motter
Ruth
R
Nguyen
Minh
M
Reed
Amanda
A
Schenk
Dale
D
Tang
Pearl
P
Vasquez
Nicki
N
Seubert
Peter
P
Yednock
Ted
T
D000544:Alzheimer Disease / Q000276:immunology / Q000517:prevention & control*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000918:Antibody Specificity; D018604:Epitope Mapping; D000939:Epitopes / Q000276:immunology*; D006801:Humans; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology*
D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D000939:Epitopes; D010446:Peptide Fragments