Human PSEN1 Mutant Glia Improve Spatial Learning and Memory in Aged Mice

Abstract

The PSEN1 ΔE9 mutation causes a familial form of Alzheimer’s disease (AD) by shifting the processing of amyloid precursor protein (APP) towards the generation of highly amyloidogenic Aβ42 peptide. We have previously shown that the PSEN1 ΔE9 mutation in human-induced pluripotent stem cell (iPSC)-derived astrocytes increases Aβ42 production and impairs cellular responses. Here, we injected PSEN1 ΔE9 mutant astrosphere-derived glial progenitors into newborn mice and investigated mouse behavior at the ages of 8, 12, and 16 months. While we did not find significant behavioral changes in younger mice, spatial learning and memory were paradoxically improved in 16-month-old PSEN1 ΔE9 glia-transplanted male mice as compared to age-matched isogenic control-transplanted animals. Memory improvement was associated with lower levels of soluble, but not insoluble, human Aβ42 in the mouse brain. We also found a decreased engraftment of PSEN1 ΔE9 mutant cells in the cingulate cortex and significant transcriptional changes in both human and mouse genes in the hippocampus, including the extracellular matrix-related genes. Overall, the presence of PSEN1 ΔE9 mutant glia exerted a more beneficial effect on aged mouse brain than the isogenic control human cells likely as a combination of several factors.

Astrocytes regulate neuronal network burst frequency through NMDA receptors species- and donor-specifically

“…Several hiPSC-based studies have demonstrated how the presence of astrocytes is required for the development of complex neuronal network-level activity in vitro (2,6,19,25). Astrocytes are also known to play a role in the pathogenesis of conditions such as schizophrenia and Alzheimer’s disease (4,9,10). Hence, there is an increasing need for the use of donor-specific astrocytes in hiPSC-based models of the brain.…”

“…This has raised a question to what extent rodent astrocytes can substitute human glial cells and recapitulate features that are relevant for human neural functions. Furthermore, an increasing number of studies has shown that astrocytes have a role in the pathogenesis of developmental (4,9) and neurodegenerative disorders (10,11). This has evidenced the need for fully human neuron-astrocyte co-cultures for modeling development and disorders of the human brain.…”

Navigating Human Astrocyte Differentiation: Direct and Rapid one-step Differentiation of Induced Pluripotent Stem Cells to Functional Astrocytes Supporting Neuronal Network development

“…Nowadays astrocytes are known to support neurons at many different levels: neurogenesis, synaptogenesis including both formation and maturation of the synapses, metabolic support, synaptic plasticity, neurotransmission including uptake of neurotransmitters, as well as support of the bloodbrain-barrier and regulation of the blood flow [3][4][5][6] . The involvement of astrocytes in the pathogenesis of neurodevelopmental and neurodegenerative disorders is becoming increasingly recognized [7][8][9][10] .…”