Amyloid-beta peptide remnants in AN-1792-immunized Alzheimer's disease patients: a biochemical analysis.
Experiments with amyloid-beta (Abeta)-42-immunized transgenic mouse models of Alzheimer's disease have revealed amyloid plaque disruption and apparent cognitive function recovery. Neuropathological examination of patients vaccinated against purified Abeta-42 (AN-1792) has demonstrated that senile plaque disruption occurred in immunized humans as well. Here, we examined tissue histology and quantified and biochemically characterized the remnant amyloid peptides in the gray and white matter and leptomeningeal/cortical vessels of two AN-1792-vaccinated patients, one of whom developed meningoencephalitis. Compact core and diffuse amyloid deposits in both vaccinated individuals were focally absent in some regions. Although parenchymal amyloid was focally disaggregated, vascular deposits were relatively preserved or even increased. Immunoassay revealed that total soluble amyloid levels were sharply elevated in vaccinated patient gray and white matter compared with Alzheimer's disease cases. Our experiments suggest that although immunization disrupted amyloid deposits, vascular capture prevented large-scale egress of Abeta peptides. Trapped, solubilized amyloid peptides may ultimately have cascading toxic effects on cerebrovascular, gray and white matter tissues. Anti-amyloid immunization may be most effective not as therapeutic or mitigating measures but as a prophylactic measure when Abeta deposition is still minimal. This may allow Abeta mobilization under conditions in which drainage and degradation of these toxic peptides is efficient.
Patton
R Lyle
RL
The Longtine Center for Molecular Biology and Genetics, W.H. Civin Laboratory for Neuropathology, M.D. Sun Health Research Institute, 10515 W. Santa Fe Dr., Sun City, AZ 85351, USA.
Kalback
Walter M
WM
Esh
Chera L
CL
Kokjohn
Tyler A
TA
Van Vickle
Gregory D
GD
Luehrs
Dean C
DC
Kuo
Yu-Min
YM
Lopez
John
J
Brune
Daniel
D
Ferrer
Isidro
I
Masliah
Eliezer
E
Newel
Amanda J
AJ
Beach
Thomas G
TG
Castaño
Eduardo M
EM
Roher
Alex E
AE
D000368:Aged; D000544:Alzheimer Disease / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D023582:Alzheimer Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D016229:Amyloid beta-Peptides / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D002540:Cerebral Cortex / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007114:Immunization / Q000009:adverse effects; D008297:Male; D008590:Meningoencephalitis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic
D023582:Alzheimer Vaccines; D016229:Amyloid beta-Peptides