Efficient derivation of cortical glutamatergic neurons from human pluripotent stem cells: a model system to study neurotoxicity in Alzheimer's disease.
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.
The Department of Chemical and Biomolecular Engineering, USA; The Department of Bioengineering, USA; Helen Wills Neuroscience Institute, USA; University of California, Berkeley, CA 94720, USA.
Tandis
T
Vazin
Graduate Group in Biophysics, USA; University of California, Berkeley, CA 94720, USA.
K Aurelia
KA
Ball
Helen Wills Neuroscience Institute, USA; Division of Neurobiology, Department of Molecular and Cell Biology, USA; University of California, Berkeley, CA 94720, USA.
Hui
H
Lu
Helen Wills Neuroscience Institute, USA; Division of Neurobiology, Department of Molecular and Cell Biology, USA; University of California, Berkeley, CA 94720, USA.
Hyungju
H
Park
Department of Molecular and Cell Biology, USA; University of California, Berkeley, CA 94720, USA.
Yasaman
Y
Ataeijannati
The Department of Chemical and Biomolecular Engineering, USA; The Department of Bioengineering, USA; Graduate Group in Biophysics, USA; Department of Chemistry, USA; University of California, Berkeley, CA 94720, USA.
Teresa
T
Head-Gordon
Helen Wills Neuroscience Institute, USA; Division of Neurobiology, Department of Molecular and Cell Biology, USA; University of California, Berkeley, CA 94720, USA.
Mu-ming
MM
Poo
The Department of Chemical and Biomolecular Engineering, USA; The Department of Bioengineering, USA; Helen Wills Neuroscience Institute, USA; University of California, Berkeley, CA 94720, USA. Electronic address: schaffer@berkeley.edu.
David V
DV
Schaffer
D000367:Age Factors; D000544:Alzheimer Disease / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D016923:Cell Death; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D005260:Female; D059330:GABAergic Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D009474:Neurons / Q000187:drug effects* / Q000473:pathology / Q000502:physiology*; D039904:Pluripotent Stem Cells / Q000166:cytology*; D011916:Rats, Inbred F344
D016229:Amyloid beta-Peptides; D053823:Hedgehog Proteins; D018698:Glutamic Acid
Alzheimer's disease; Amyloid beta; Cortical; Glutamatergic; Human; In vitro model; Neuron; Pluripotent; Stem cell