Aβ immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome

Salvatore - Oddo, Lauren Billings, J. Patrick Kesslak, David H. Cribbs, Frank M. LaFerla

Research output: Contribution to journalArticle

672 Citations (Scopus)

Abstract

Amyloid-β (Aβ) 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 Aβ clearance on the development of tau pathology. Here we show that Aβ immunotherapy reduces not only extracellular Aβ plaques but also intracellular Aβ accumulation and most notably leads to the clearance of early tau pathology. We find that Aβ deposits are cleared first and subsequently reemerge prior to the tau pathology, indicative of a hierarchical and direct relationship between Aβ 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 Aβ antibody treatment. These findings indicate that Aβ immunization may be useful for clearing both hallmark lesions of AD, provided that intervention occurs early in the disease course.

Original languageEnglish (US)
Pages (from-to)321-332
Number of pages12
JournalNeuron
Volume43
Issue number3
DOIs
StatePublished - Aug 5 2004
Externally publishedYes

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Proteasome Endopeptidase Complex
Immunotherapy
Alzheimer Disease
Pathology
Neurofibrillary Tangles
Amyloid Plaques
Immunization
Phosphorylation
Antibodies
Brain
Therapeutics

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Aβ immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. / Oddo, Salvatore -; Billings, Lauren; Kesslak, J. Patrick; Cribbs, David H.; LaFerla, Frank M.

In: Neuron, Vol. 43, No. 3, 05.08.2004, p. 321-332.

Research output: Contribution to journalArticle

Oddo, Salvatore - ; Billings, Lauren ; Kesslak, J. Patrick ; Cribbs, David H. ; LaFerla, Frank M. / Aβ immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. In: Neuron. 2004 ; Vol. 43, No. 3. pp. 321-332.
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