Extracellular association of APP and tau fibrils induces intracellular aggregate formation of tau.

Muneaki Takahashi,Takashi Nonaka,Fuyuki Kametani,Haruhiko Akiyama,Shin-Ichi Hisanaga,Masato Hasegawa,Haruka Miyata

doi:10.1007/s00401-015-1415-2

Abstract

Alzheimer’s disease (AD) is characterized by extracellular amyloid β (Aβ) deposition and intracellular tau aggregation. Many studies have indicated some association between these processes, but it remains unknown how the two pathologies are linked. In this study, we investigated whether expression of amyloid precursor protein (APP) influences extracellular seed-dependent intracellular tau accumulation in cultured cells. Treatment of tau-expressing SH-SY5Y cells with Aβ fibrils did not induce intracellular tau aggregation. On the other hand, in cells expressing both tau and APP, treatment with tau fibrils or Sarkosyl-insoluble tau from AD brains induced intracellular tau aggregation. The seed-dependent intracellular tau aggregation was not induced by expression of APP lacking the extracellular domain. The amount of phosphorylated tau aggregates in cultured cells was dose dependently elevated in response to increased levels of APP on the cell membrane. Our results indicate that the extracellular region of APP is involved in uptake of tau fibrils into cells, raising the possibility that APP, but not Aβ, influences cell-to-cell spreading of tau pathologies in AD by serving as a receptor of abnormal tau aggregates.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-015-1415-2) contains supplementary material, which is available to authorized users.

Highlights

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, characterized by the deposition of two kinds of filamentous aggregates: extracellular senile plaque consisting of amyloid β (Aβ) and intracellular paired helical filaments consisting of tau proteins
Strong tau staining was observed on amyloid precursor protein (APP)-expressing cells by incubation with tau fibrils, and this staining was colocalized with APP staining (Fig. 1e)
We show that overexpressed APP on the cell surface associates with tau fibrils and accelerates intracellular tau aggregation, and that both recombinant tau fibrils and pathological tau-enriched Sarkosyl-insoluble fraction from AD brains can induce intracellular tau aggregation in association with APP

Summary

Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, characterized by the deposition of two kinds of filamentous aggregates: extracellular senile plaque consisting of amyloid β (Aβ) and intracellular paired helical filaments consisting of tau proteins. Several missense mutations of the APP gene at or near the cleavage sites cause Aβ production in familial forms of AD [4, 11, 40, 41]. Six tau isoforms are expressed by alternative splicing of the mRNA in adult human brain, but in AD, all these tau isoforms are accumulated in hyperphosphorylated and partially ubiquitinated forms as a unique paired helical filament (PHF) structure in neurofibrillary tangles and threads. Both Aβ and tau fibrils in AD brains have a cross-β structure similar to that of abnormal prion protein in Creutzfeldt–Jakob disease [20]. The distribution and spreading of abnormal tau pathology in AD are

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Conclusion