Efficient derivation of cortical glutamatergic neurons from human pluripotent stem cells: A model system to study neurotoxicity in Alzheimer's disease

Abstract

Alzheimer's disease (AD) is among the most prevalent forms of dementia affecting the aging population, and pharmacological therapies to date have not been successful in preventing disease progression. Future therapeutic efforts may benefit from the development of models that enable basic investigation of early disease pathology. In particular, disease-relevant models based on human pluripotent stem cells (hPSCs) may be promising approaches to assess the impact of neurotoxic agents in AD on specific neuronal populations and thereby facilitate the development of novel interventions to avert early disease mechanisms. We implemented an efficient paradigm to convert hPSCs into enriched populations of cortical glutamatergic neurons emerging from dorsal forebrain neural progenitors, aided by modulating Sonic hedgehog (Shh) signaling. Since AD is generally known to be toxic to glutamatergic circuits, we exposed glutamatergic neurons derived from hESCs to an oligomeric pre-fibrillar forms of Aβ known as “globulomers”, which have shown strong correlation with the level of cognitive deficits in AD. Administration of such Aβ oligomers yielded signs of the disease, including cell culture age-dependent binding of Aβ and cell death in the glutamatergic populations. Furthermore, consistent with previous findings in postmortem human AD brain Aβ-induced toxicity was selective for glutamatergic rather than GABAeric neurons present in our cultures. This in vitro model of cortical glutamatergic neurons thus offers a system for future mechanistic investigation and therapeutic development for AD pathology using human cell types specifically affected by this disease.

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

“…Furthermore, genetic and epigenetic variability among patients may influence pharmacological responsiveness [45]. Disease modeling using iPS cells for AD has been actively pursued recently and has shown that pharmacological assays can be readily performed using these models [46][47][48][49][50][51][52]. Modeling and screening using glial-neuron coculture and 3-dimensional cultures, both of which better resemble in vivo physiological states, should also be pursued [53,54].…”

Neural patterning of human induced pluripotent stem cells in 3-D cultures for studying biomolecule-directed differential cellular responses

“…The diversity of human brain cell subtypes results in the selective cell death or region/circuit-specific dysfunctions in a variety of neurological diseases [9,65]. However, numerous neuronal subtypes, complicated cellular interactions, and diverse genetic background of the patients pose a difficulty for drug development and disease modeling.…”

“…While some disease progressions (e.g., amyloid-β plaques) may take years, in vitro neural models derived from hiPSCs can be used to probe disease on-set and development in a shortened time frame [8]. Another advantage of in vitro models derived from hiPSCs is the ability to generate specific neuronal subtypes, which are known to exhibit differential susceptibility to diseasespecific molecules [9,10]. For example, cortical neurons derived from hiPSCs have been used to screen anti-amyloid β (Aβ) drugs and to evaluate Aβ-induced toxicity [9,11,12].…”

“…Another advantage of in vitro models derived from hiPSCs is the ability to generate specific neuronal subtypes, which are known to exhibit differential susceptibility to diseasespecific molecules [9,10]. For example, cortical neurons derived from hiPSCs have been used to screen anti-amyloid β (Aβ) drugs and to evaluate Aβ-induced toxicity [9,11,12]. Moreover, hiPSC-derived motor neurons have been derived to model a variety of motor neuron diseases, such as amyotrophic lateral sclerosis (ALS) [5,13].…”

Advances in Reprogramming-Based Study of Neurologic Disorders

“…One method to produce human neurons suitable for disease modeling is by differentiating human iPSCs (hiPSCs) or human embryonic stem cells (hESCs) into desired neural lineages, such as cortical pyramidal neurons, striatal interneurons, motor neurons, or dopaminergic neurons [31][32][33][34][35][36][37][38][39][40][41][42]. Importantly, hiPSC-derived neurons are functionally active, and can respond to synaptic stimulation and specific sensory response-evoking ligands [43][44][45][46][47][48][49].…”