Blocking Abeta42 accumulation delays the onset and progression of tau pathology via the C terminus of heat shock protein70-interacting protein: a mechanistic link between Abeta and tau pathology.
The molecular alterations that induce tau pathology in Alzheimer disease (AD) are not known, particularly whether this is an amyloid-beta (Abeta)-dependent or -independent event. We addressed this issue in the 3xTg-AD mice using both genetic and immunological approaches and show that a selective decrease in Abeta(42) markedly delays the progression of tau pathology. The mechanism underlying this effect involves alterations in the levels of C terminus of heat shock protein70-interacting protein (CHIP) as we show that Abeta accumulation decreases CHIP expression and increases tau levels. We show that the Abeta-induced effects on tau were rescued by restoring CHIP levels. Our findings have profound clinical implications as they indicate that preventing Abeta accumulation will significantly alter AD progression. These data highlight the critical role CHIP plays as a link between Abeta and tau and identify CHIP as a new potential target not only for AD but for other neurodegenerative disorders characterized by tau accumulation.
Oddo
Salvatore
S
Department of Neurobiology and Behavior, University of California, Irvine, Irvine, California 92697, USA.
Caccamo
Antonella
A
Tseng
Bert
B
Cheng
David
D
Vasilevko
Vitaly
V
Cribbs
David H
DH
LaFerla
Frank M
FM
D000367:Age Factors; D017668:Age of Onset; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism; D003072:Cognition Disorders / Q000209:etiology / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000502:physiology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D034741:RNA, Small Interfering; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases