Pathological manifestation of the induced pluripotent stem cell-derived cortical neurons from an early-onset Alzheimer's disease patient carrying a presenilin-1 mutation (S170F).

Ling Li,Minchul Kim,Hyohoon Heo,Wonyoung Koh,Chang Pyo Hong,Mahito Nakanishi,Jaehoon Chung,Taeyoung Yoon,Sang Won Seo,Younghoon Kim,Jihwan Song,Jee Hoon Roh,Hee Jin Kim,Duk L Na

doi:10.1111/cpr.12798

Abstract

ObjectivesAlzheimer's disease (AD) is the most common neurodegenerative disease which is characterized by the formation of amyloid beta (Aβ) plaques and neurofibrillary tangles. These abnormal proteins induce disturbance in mitochondrial dynamics and defect in autophagy system. Since presenilin‐1 (PS1) is a core component in γ‐secretase complex, the mutations of PS1 gene cause the interference of γ‐secretase activity and lead to the increased Aβ42 secretion. We aimed to characterize the patient‐specific induced pluripotent stem cell (iPSC) line carrying PS1‐S170F mutation. Furthermore, we tested whether disease‐modifying drug can reduce AD pathology in the AD iPSC‐derived neurons.Materials and methodsMononuclear cells (MNCs) were isolated freshly from the peripheral blood of an autosomal dominant AD (ADAD) patient carrying presenilin‐1 (PS1) mutation (Ser170Phe; PS1‐S170F) and a cognitively normal control. We generated induced pluripotent stem cell (iPSC) lines, which were differentiated into functional cortical neurons. Then, we measured the markers indicative of AD pathogenesis using immunocytochemistry and Western blot. We also investigated the mitochondrial dynamics in the AD iPSC‐derived neurons using Mito‐tracker.ResultsWe observed that both extracellular and intracellular Aβ levels were dramatically increased in the PS1‐S170F iPSC‐derived neurons, compared with the control iPSC‐derived neurons. Furthermore, PS1‐S170F iPSC‐derived neurons showed high expression levels of p‐Tau, which were detected both in the soma and neurites. The mitochondrial velocity in the PS1‐S170F iPSC‐derived neurons was much reduced, compared with that of the control. We also found a significant decrease of fusion‐related protein Mfn1 (membrane proteins mitofusin 1) and an increase of fission‐related protein DRP1 (dynamin‐related protein 1) in the PS1‐S170F iPSC‐derived neurons. We further observed the defects of autophagy‐related clearance in the PS1‐S170F iPSC‐derived neurons. Finally, we demonstrated the levels of Aβ and p‐Tau can be dramatically reduced by the treatment of LY‐2886721, a BACE1 inhibitor.ConclusionsTaken together, we have established and characterized the pathological features of an AD patient carrying PS1‐S170F mutation using iPSC technology, which will be the first case on this mutation and this iPSC line will serve as a useful resource for studying AD pathogenesis and drug screening in the future.

Highlights

Alzheimer's disease (AD) is the most common cause of dementia, which is pathologically defined by the accumulation of extracellular amyloid plaques and intraneuronal hyperphosphorylated tau aggregates associated with neuronal loss in the cerebral cortex.[1,2]
DRP1 expression levels were significantly increased in the PS1-S170F induced pluripotent stem cell (iPSC)-derived neurons, compared with that of the control (Figure 3D,E). These results strongly suggest that high levels of Aβ and phosphorylated tau (p-Tau) may disrupt the mitochondrial transport, through impaired balance of mitochondrial fusion and fission in the PS1S170F iPSC-derived neurons
In an attempt to understand AD pathogenesis, we have established and characterized the patient iPSC line from an AD patient carrying PS1-S170F mutation

Summary

Introduction

Alzheimer's disease (AD) is the most common cause of dementia, which is pathologically defined by the accumulation of extracellular amyloid plaques and intraneuronal hyperphosphorylated tau aggregates associated with neuronal loss in the cerebral cortex.[1,2] Autosomal dominant AD (ADAD) is associated with mutations in presenilin-1 (PS1), presenilin-2 (PS2) or amyloid precursor protein (APP) genes. Alzheimer's disease (AD) is the most common cause of dementia, which is pathologically defined by the accumulation of extracellular amyloid plaques and intraneuronal hyperphosphorylated tau aggregates associated with neuronal loss in the cerebral cortex.[1,2]. Autosomal dominant AD (ADAD) is associated with mutations in presenilin-1 (PS1), presenilin-2 (PS2) or amyloid precursor protein (APP) genes. The S170F in the PS1 gene is a wellknown mutation causing AD at very young age (ie third decade of life) with a rapid progression.[3-5]. We chose this mutation to generate iPSCs, because it is one of the most aggressive forms of AD both clinically and pathologically. We speculated that the iPSC-derived neurons from this patient would exhibit AD pathology, including significant defects in mitochondrial and autophagy systems

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