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

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.