Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome.
Amyloid-beta (Abeta) plaques and neurofibrillary tangles are the hallmark neuropathological lesions of Alzheimer's disease (AD). Using a triple transgenic model (3xTg-AD) that develops both lesions in AD-relevant brain regions, we determined the consequence of Abeta clearance on the development of tau pathology. Here we show that Abeta immunotherapy reduces not only extracellular Abeta plaques but also intracellular Abeta accumulation and most notably leads to the clearance of early tau pathology. We find that Abeta deposits are cleared first and subsequently reemerge prior to the tau pathology, indicative of a hierarchical and direct relationship between Abeta and tau. The clearance of the tau pathology is mediated by the proteasome and is dependent on the phosphorylation state of tau, as hyperphosphorylated tau aggregates are unaffected by the Abeta antibody treatment. These findings indicate that Abeta immunization may be useful for clearing both hallmark lesions of AD, provided that intervention occurs early in the disease course.
Oddo
Salvatore
S
Institute for Brain Aging and Dementia, University of California, Irvine, Irvine, CA 92697, USA.
Billings
Lauren
L
Kesslak
J Patrick
JP
Cribbs
David H
DH
LaFerla
Frank M
FM
D000544:Alzheimer Disease / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000628:therapy; D023582:Alzheimer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D016229:Amyloid beta-Peptides / Q000008:administration & dosage* / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000276:immunology; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D045604:Extracellular Fluid / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007276:Injections, Intraventricular; D007424:Intracellular Fluid / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009097:Multienzyme Complexes / Q000378:metabolism*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; D016875:tau Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D023582:Alzheimer Vaccines; D016229:Amyloid beta-Peptides; D000906:Antibodies; D009097:Multienzyme Complexes; D016875:tau Proteins; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex