title: Inhibitory interneuron progenitor transplantation restores normal learning and memory in ApoE4 knock-in mice without or with Aβ accumulation.
abstract: Excitatory and inhibitory balance of neuronal network activity is essential for normal brain function and may be of particular importance to memory. Apolipoprotein (apo) E4 and amyloid-β (Aβ) peptides, two major players in Alzheimer's disease (AD), cause inhibitory interneuron impairments and aberrant neuronal activity in the hippocampal dentate gyrus in AD-related mouse models and humans, leading to learning and memory deficits. To determine whether replacing the lost or impaired interneurons rescues neuronal signaling and behavioral deficits, we transplanted embryonic interneuron progenitors into the hippocampal hilus of aged apoE4 knock-in mice without or with Aβ accumulation. In both conditions, the transplanted cells developed into mature interneurons, functionally integrated into the hippocampal circuitry, and restored normal learning and memory. Thus, restricted hilar transplantation of inhibitory interneurons restores normal cognitive function in two widely used AD-related mouse models, highlighting the importance of interneuron impairments in AD pathogenesis and the potential of cell replacement therapy for AD. More broadly, it demonstrates that excitatory and inhibitory balance are crucial for learning and memory, and suggests an avenue for investigating the processes of learning and memory and their alterations in healthy aging and diseases.
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California 94158, Biomedical Sciences Graduate Program.
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Tong
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California 94158, Departments of Neurology.
authors.forename: Biljana
authors.initials: B
authors.lastname: Djukic
authors.affiliation: Departments of Neurology, Psychiatry, Neurological Surgery, and.
authors.forename: Christine
authors.initials: C
authors.lastname: Arnold
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California 94158, Biomedical Sciences Graduate Program.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Gillespie
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California 94158.
authors.forename: Seo Yeon
authors.initials: SY
authors.lastname: Yoon
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California 94158.
authors.forename: Max M
authors.initials: MM
authors.lastname: Wang
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California 94158.
authors.forename: Olivia
authors.initials: O
authors.lastname: Zhang
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California 94158, Departments of Neurology.
authors.forename: Johanna
authors.initials: J
authors.lastname: Knoferle
authors.affiliation: Psychiatry.
authors.forename: John L R
authors.identifier: http://orcid.org/0000-0002-4414-7667
authors.initials: JL
authors.lastname: Rubenstein
authors.affiliation: Departments of Neurology, Neurological Surgery, and The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California 94143.
authors.forename: Arturo
authors.initials: A
authors.lastname: Alvarez-Buylla
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California 94158, Biomedical Sciences Graduate Program, Departments of Neurology, Pathology, and yhuang@gladstone.ucsf.edu.
authors.forename: Yadong
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000503:physiopathology / Q000601:surgery; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D053327:Apolipoprotein E4 / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D066298:In Vitro Techniques; D007395:Interneurons / Q000502:physiology*; D007858:Learning / Q000502:physiology*; D008297:Male; D018782:Maze Learning; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D058953:Neural Stem Cells / Q000637:transplantation*
chemical_list: D016564:Amyloid beta-Protein Precursor; D053327:Apolipoprotein E4; D009419:Nerve Tissue Proteins
keywords: Alzheimer's disease; MGE-derived GABAergic progenitor; apoE; apoE knock-in mice; cell transplantation; learning and memory