Abstract
Alzheimer’s disease (AD) pathology is characterized by the aggregation of beta-amyloid (Aβ) and tau in the form of amyloid plaques and neurofibrillary tangles in the brain. It has been found that a synergistic relationship between these two proteins may contribute to their roles in disease progression. However, how Aβ and tau interact has not been fully characterized. Here, we analyze how tau seeding or aggregation is influenced by different Aβ self-assemblies (fibrils and oligomers). Our cellular assays utilizing tau biosensor cells show that transduction of Aβ oligomers into the cells greatly enhances seeded tau aggregation in a concentration-dependent manner. In contrast, transduced Aβ fibrils slightly reduce tau seeding while untransduced Aβ fibrils promote it. We also observe that the transduction of α-synuclein fibrils, another amyloid protein, has no effect on tau seeding. The enhancement of tau seeding by Aβ oligomers was confirmed using tau fibril seeds derived from both recombinant tau and PS19 mouse brain extracts containing human tau. Our findings highlight the importance of considering the specific form and cellular location of Aβ self-assembly when studying the relationship between Aβ and tau in future AD therapeutic development.
Highlights
The accumulation of amyloid plaques and neurofibrillary tangles in the brain are the two major hallmarks of Alzheimer’s disease (AD) and are composed of the aggregated proteins β-amyloid (Aβ) and tau, respectively
R (A) Tau seeding of biosensor cells pretreated with transduced α-synuclein fibrils or Aβ oligomers as measured by Integrated FRET Density (IFD). (B) Representative fluorescent images of treated tau biosensor cells
Our experiments quantitatively study the effects of different Aβ aggregates on tau seeding, another important contributor to AD pathology
Summary
The accumulation of amyloid plaques and neurofibrillary tangles in the brain are the two major hallmarks of Alzheimer’s disease (AD) and are composed of the aggregated proteins β-amyloid (Aβ) and tau, respectively. Images of the biosensor cells seeded with tau RD (10 nM) show intracellular tau aggregates in the form of bright fluorescent puncta (Figure 1C). The effects of each Aβ species on tau seeding are much more pronounced with higher tau seed concentrations: Aβ oligomers enhance seeding, Aβ fibrils have an inhibitory effect, measure the unique contributions of different assemblies of Aβ – and freshly prepared Aβ has little effect (Figure 1E). Self-assemblies on intracellular tau seeding, we first generated We further analyzed the effects of Aβ oligomers on the and characterized three forms of Aβ self-assemblies: freshly promotion of tau seeding with a broader range of tau fibril prepared, oligomeric, and fibrillar. Following the observation that Aβ oligomers enhance biosensor cell seeding with recombinant tau RD, we determined whether other forms of tau seeds lead to similar effects. Similar to recombinant tau RD, the mouse brain extract seeding was greatly enhanced by pretreatment with Aβ oligomers (Figure 3)
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