Human Pluripotent Stem Cell-Derived Neural Cells as a Relevant Platform for Drug Screening in Alzheimer's Disease

Abstract

Extracellular amyloid-beta deposition and intraneuronal Tau-laden neurofibrillary tangles are prime features of Alzheimer's disease (AD). The pathology of AD is very complex and still not fully understood, since different neural cell types are involved in the disease. Although neuronal function is clearly deteriorated in AD patients, recently, an increasing number of evidences have pointed towards glial cell dysfunction as one of the main causative phenomena implicated in AD pathogenesis. The complex disease pathology together with the lack of reliable disease models have precluded the development of effective therapies able to counteract disease progression. The discovery and implementation of human pluripotent stem cell technology represents an important opportunity in this field, as this system allows the generation of patient-derived cells to be used for disease modeling and therapeutic target identification and as a platform to be employed in drug discovery programs. In this review, we discuss the current studies using human pluripotent stem cells focused on AD, providing convincing evidences that this system is an excellent opportunity to advance in the comprehension of AD pathology, which will be translated to the development of the still missing effective therapies.

Keywords: 3D cultures; Alzheimer’s disease; astrocytes; brain organoids; disease modeling; human induced pluripotent stem cells (hiPSCs); microglia; oligodendrocytes.

Figure 1

(A) The two most used approaches for the derivation of human pluripotent stem cell (hPSC)-derived neurons are represented: dual SMAD (Caenorhabditis elegans Sma genes and the Drosophila Mad, Mothers against decapentaplegic) inhibition-based protocols (above) and direct generation of neurons by the exogenous overexpression of NGN2 (below). (B) The main phenotypes encountered in neurons derived from iPSCs of AD patients are presented. hPSCs: human pluripotent stem cells; iPSCs: induced pluripotent stem cells; bFGF: basic fibroblast growth factor; SMAD: Caenorhabditis elegans Sma genes and the Drosophila Mad, Mothers against decapentaplegic; NGN2: neurogenin 2; NPCs: neural precursor cells; Aβ: amyloid beta; AD: Alzheimer’s disease.

Figure 2

(A) The two most used approaches for the derivation of hPSC-derived astrocytes are represented: dual SMAD inhibition-based protocols and expansion of glial precursor cells (GPCs) (above) and direct generation of astrocytes by the exogenous overexpression of NFIA/B plus SOX9 (below). (B) The main phenotypes encountered in astrocytes derived from iPSCs of AD patients are presented. hPSCs: human pluripotent stem cells; iPSCs: induced pluripotent stem cells; bFGF: basic fibroblast growth factor; EGF: epidermal growth factor; BMP4: Bone morphogenetic protein 4; CNTF: Ciliary Neurotrophic Factor; FBS: Fetal Bovine Serum; NPCs: neural precursor cells; GPCs: glial precursor cells; Aβ: amyloid beta; AD: Alzheimer’s disease.

Figure 3

(A) The two most used approaches for the derivation of hPSC-derived oligodendrocytes (OLs) are represented: glial induction by dual SMAD inhibition in the presence of specific morphogens such as retinoic acid (RA) and sonic hedgehog (Shh); expansion of the oligodendrocyte precursor cells (OPCs) in the presence of platelet-derived growth factor (PDGF) and insulin growth factor 1 (IGF-1); terminal differentiation by the withdrawal of mitogens and addition of T3, NT-3, and ascorbic acid (above); and direct generation of OLs by the exogenous overexpression of SOX10 on glial precursor cells (GPCs) (below). (B) The main phenotypes present in OLs from AD patients and models are presented. hPSCs: human pluripotent stem cells; iPSCs: induced pluripotent stem cells; RA: retinoic acid; Shh: sonic hedgehog; PDGF: platelet-derived growth factor; IGF-1: insulin growth factor 1; NT-3: neurotrophin 3; T3: triiodothyronine; AA: ascorbic acid; OPCs: oligodendrocyte precursor cells; GPCs: glial precursor cells; OLs: oligodendrocytes; AD: Alzheimer’s disease.

Figure 4

The most used protocol for the generation of microglia from hPSCs (A) and the main phenotypes encountered in microglia derived from iPSCs of AD patients (B). hPSCs: human pluripotent stem cells; iPSCs: induced pluripotent stem cells; bFGF: basic fibroblast growth factor; BMP4: Bone morphogenetic protein 4; VEGF: Vascular Endothelial Growth Factor; MCSF: Macrophage Colony Stimulating Factor; IL-34: interleukin 34; MPs: myeloid precursor cells; Aβ: amyloid beta; AD: Alzheimer’s disease.

Figure 5

The most used protocol for the generation of brain organoids or 3D neural cell cultures from hPSCs (A) and the main phenotypes encountered in organoids or 3D cultures derived from iPSCs of AD patients (B). hPSCs: human pluripotent stem cells; iPSCs: induced pluripotent stem cells; bFGF: basic fibroblast growth factor; ROCK: Rho kinase; NPCs: neural precursor cells; Aβ: amyloid beta; AD: Alzheimer’s disease.