Induced Pluripotent Stem Cell-Derived Neural Precursors Improve Memory, Synaptic and Pathological Abnormalities in a Mouse Model of Alzheimer's Disease.

Enrique Armijo,Magdalena Sanhueza,Fabio Moda,Jorge Vera,Cesar Gonzalez,George Edwards,Claudio Soto,Andrea Flores,Mohammad Shahnawaz

doi:10.3390/cells10071802

Abstract

Alzheimer’s disease (AD) is the most common type of dementia in the elderly population. The disease is characterized by progressive memory loss, cerebral atrophy, extensive neuronal loss, synaptic alterations, brain inflammation, extracellular accumulation of amyloid-β (Aβ) plaques, and intracellular accumulation of hyper-phosphorylated tau (p-tau) protein. Many recent clinical trials have failed to show therapeutic benefit, likely because at the time in which patients exhibit clinical symptoms the brain is irreversibly damaged. In recent years, induced pluripotent stem cells (iPSCs) have been suggested as a promising cell therapy to recover brain functionality in neurodegenerative diseases such as AD. To evaluate the potential benefits of iPSCs on AD progression, we stereotaxically injected mouse iPSC-derived neural precursors (iPSC-NPCs) into the hippocampus of aged triple transgenic (3xTg-AD) mice harboring extensive pathological abnormalities typical of AD. Interestingly, iPSC-NPCs transplanted mice showed improved memory, synaptic plasticity, and reduced AD brain pathology, including a reduction of amyloid and tangles deposits. Our findings suggest that iPSC-NPCs might be a useful therapy that could produce benefit at the advanced clinical and pathological stages of AD.

Highlights

Introduction iationsAlzheimer’s disease (AD) is a common, progressive, and devastating neurodegenerative disease characterized by memory impairment and cognitive decline [1]
Cells were characterized by immunocytochemistry using various markers for embryonic stem cells, room temperature (RT)-PCR to analyze the level of expression of stem cell markers, and a pluripotency assay to show that induced pluripotent stem cells (iPSCs) can originate cells from the three germ layers (Figure S1)
Engrafted iPSC-NPCs were observed to differentiate into the three neural lineages in a manner similar to reports for fetal neural stem cells (NSCs) [33,34,35], namely: Astrocytes co-expressing green fluorescent protein (GFP) and glial fibrillary acidic protein (GFAP) (30.4% ± 3.8; Figure 1c); neurons co-expressing GFP and the early neuronal marker DCX (4.8% ± 2.0; Figure 1d); and oligodendrocytes co-expressing GFP and 20,30 -cyclic nucleotide-30 phosphodiesterase (CNPase; 1.4% ± 0.6; Figure 1e)

Summary

Introduction

Alzheimer’s disease (AD) is a common, progressive, and devastating neurodegenerative disease characterized by memory impairment and cognitive decline [1]. The most prominent pathological hallmarks of the disease are the extracellular deposition of amyloid β (Aβ) peptides in the form of amyloid plaques and the intracellular accumulation of hyperphosphorylated tau (p-tau) proteins in the form of neurofibrillary tangles (NFTs). AD represents a tremendous socio-economic problem due to its devastating nature, monetary cost, and the lack of effective therapies. The search for an efficient treatment for this devastating disease is an urgent medical priority [3,4].

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Conclusion