Aβ-induced acceleration of Alzheimer-related τ-pathology spreading and its association with prion protein

Extracellular deposition of amyloid beta-protein (A beta) in amyloid plaques and intracellular accumulation of abnormally phosphorylated tau-protein (p-tau) in neurofibrillary tangles (NFTs) represent pathological hallmark lesions of Alzheimer's disease (AD). Both lesions develop in parallel in the human brain throughout the preclinical and clinical course of AD. Nevertheless, it is not yet clear whether there is a direct link between A beta and tau pathology or whether other proteins are involved in this process. To address this question, we crossed amyloid precursor protein (APP) transgenic mice overexpressing human APP with the Swedish mutation (670/671 KM -> NL) (APP23), human wild-type APP (APP51/16), or a proenkephalin signal peptide linked to human A beta(42) (APP48) with tau-transgenic mice overexpressing human mutant 4-repeat tau-protein with the P301S mutation (TAU58). In 6-month-old APP23xTAU58 and APP51/16xTAU58 mice, soluble A beta was associated with the aggravation of p-tau pathology propagation into the CA1/subiculum region, whereas 6-month-old TAU58 and APP48xTAU58 mice neither exhibited significant amounts of p-tau pathology in the CA1/subiculum region nor displayed significant levels of soluble A beta in the forebrain. In APP23xTAU58 and APP51/16xTAU58 mice showing an acceleration of p-tau propagation, A beta and p-tau were co-immunoprecipitated with cellular prion protein (PrP). A similar interaction between PrP, p-tau and A beta was observed in human AD brains. This association was particularly noticed in 60% of the symptomatic AD cases in our sample, suggesting that PrP may play a role in the progression of AD pathology. An in vitro pull-down assay confirmed that PrP is capable of interacting with A beta and p-tau. Using a proximity ligation assay, we could demonstrate proximity (less than 30-40 nm distance) between PrP and A beta and between PrP and p-tau in APP23xTAU58 mouse brain as well as in human AD brain. Proximity between PrP and p-tau was also seen in APP51/16xTAU58, APP48xTAU58, and TAU58 mice. Based on these findings, it is tempting to speculate that PrP is a critical player in the interplay between A beta and p-tau propagation at least in a large group of AD cases. Preexisting p-tau pathology interacting with PrP, thereby, appears to be a prerequisite for A beta to function as a p-tau pathology accelerator via PrP.