The role of astrocytes in apoE4 related neurodegeneration.
Final Report Abstract
Apolipoprotein (apo) E4 is the most common risk factor for sporadic Alzheimer’s disease (AD) so far identified and is associated with age-dependent decline of learning and memory in humans. In the CNS, apoE is mainly expressed by astrocytes, but also can be expressed in microglia, smooth muscle cells and neurons after injury. To determine whether the detrimental effects of apoE4 depend on its cellular sources, I generated human apoE knock-in mouse models in which the human APOE gene is conditionally deleted in astrocytes, neurons, or GABAergic interneurons. I found that deletion of apoE4 in astrocytes does not protect aged mice from apoE4-induced GABAergic interneuron loss and learning and memory deficits. In contrast, deletion of apoE4 in neurons does protect aged mice from both deficits. Furthermore, deletion of apoE4 in GABAergic interneurons is sufficient to gain similar protection. This study demonstrates a detrimental effect of endogenously produced apoE4 on GABAergic interneurons that leads to learning and memory deficits in mice and provides a novel target for drug development for AD related to apoE4.
Publications
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(2013). Cellular source-specific effects of apolipoprotein (apo) E4 on dendrite arborization and dendritic spine development. PloS One 8, e59478
Jain, S., Yoon, S.Y., Leung, L., Knoferle, J., and Huang, Y.
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(2014). Apolipoprotein e4 produced in GABAergic interneurons causes learning and memory deficits in mice. The Journal of Neuroscience 34, 14069-14078
Knoferle, Johanna; Yoon, Seo Yeon; Walker, David; Leung, Laura; Gillespie, Anna K.; Tong, Leslie M.; Bien-Ly, Nga & Huang, Yadong
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(2014). Inhibitory interneuron progenitor transplantation restores normal learning and memory in ApoE4 knock-in mice without or with Abeta accumulation. The Journal of Neuroscience 34, 9506-9515
Tong, Leslie M.; Djukic, Biljana; Arnold, Christine; Gillespie, Anna K.; Yoon, Seo Yeon; Wang, Max M.; Zhang, Olivia; Knoferle, Johanna; Rubenstein, John L.R.; Alvarez-Buylla, Arturo & Huang, Yadong
