Maternal choline supplementation protects against age-associated cholinergic and GABAergic basal forebrain neuron degeneration in the Ts65Dn mouse model of Down syndrome and Alzheimer's disease

Megan K. Gautier, Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY, USA; Pathobiology and Translational Medicine Program, New York University Grossman School of Medicine, New York, NY, USA; NYU Neuroscience Institute, New York University Grossman School of Medicine, New York, NY, USA.
Christy M. Kelley, Complex Adaptive Systems Initiative, Arizona State University, Tempe, AZ, USA; Institute for Future Health, Scottsdale, AZ, USA.
Sang Han Lee, Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY, USA; Department of Child and Adolescent Psychiatry, New York University Grossman School of Medicine, New York, NY, USA.
Melissa J. Alldred, Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY, USA; Department of Psychiatry, New York University Grossman School of Medicine, New York, NY, USA.
John McDaid, Center for Neurodegenerative Disease and Therapeutics, Rosalind Franklin University/The Chicago Medical School, North Chicago, IL, USA.
Elliott J. Mufson, Departments of Translational Neuroscience and Neurology, Barrow Neurological Institute, Phoenix, AZ, USA.Follow
Grace E. Stutzmann, Center for Neurodegenerative Disease and Therapeutics, Rosalind Franklin University/The Chicago Medical School, North Chicago, IL, USA.
Stephen D. Ginsberg, Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY, USA; NYU Neuroscience Institute, New York University Grossman School of Medicine, New York, NY, USA; Department of Psychiatry, New York University Grossman School of Medicine, New York, NY, USA; Department of Neuroscience & Physiology, New York University Grossman School of Medicine, New York, NY, USA. Electronic address: ginsberg@nki.rfmh.org.

Document Type

Article

Abstract

Down syndrome (DS) is a genetic disorder caused by triplication of human chromosome 21. In addition to intellectual disability, DS is defined by a premature aging phenotype and Alzheimer's disease (AD) neuropathology, including septohippocampal circuit vulnerability and degeneration of basal forebrain cholinergic neurons (BFCNs). The Ts65Dn mouse model recapitulates key aspects of DS/AD pathology, namely age-associated atrophy of BFCNs and cognitive decline in septohippocampal-dependent behavioral tasks. We investigated whether maternal choline supplementation (MCS), a well-tolerated treatment modality, protects vulnerable BFCNs from age- and genotype-associated degeneration in trisomic offspring. We also examined the effect of trisomy, and MCS, on GABAergic basal forebrain parvalbumin neurons (BFPNs), an unexplored neuronal population in this DS model. Unbiased stereological analyses of choline acetyltransferase (ChAT)-immunoreactive BFCNs and parvalbumin-immunoreactive BFPNs were conducted using confocal z-stacks of the medial septal nucleus and the vertical limb of the diagonal band (MSN/VDB) in Ts65Dn mice and disomic (2N) littermates at 3-4 and 10-12 months of age. MCS trisomic offspring displayed significant increases in ChAT-immunoreactive neuron number and density compared to unsupplemented counterparts, as well as increases in the area of the MSN/VDB occupied by ChAT-immunoreactive neuropil. MCS also rescued BFPN number and density in Ts65Dn offspring, a novel rescue of a non-cholinergic cell population. Furthermore, MCS prevented age-associated loss of BFCNs and MSN/VDB regional area in 2N offspring, indicating genotype-independent neuroprotective benefits. These findings demonstrate MCS provides neuroprotection of vulnerable BFCNs and non-cholinergic septohippocampal BFPNs, indicating this modality has translational value as an early life therapy for DS, as well as extending benefits to the aging population at large.

Keywords

Alzheimer's disease, Basal forebrain cholinergic neurons, Down syndrome, Maternal choline supplementation, Medial septum, Parvalbumin, Stereology

Medical Subject Headings

Humans; Animals; Mice; Aged; Down Syndrome; Alzheimer Disease; Basal Forebrain; Parvalbumins; GABAergic Neurons; Choline O-Acetyltransferase; Disease Models, Animal; Nerve Degeneration; Dietary Supplements; Choline

Publication Date

11-1-2023

Publication Title

Neurobiology of disease

E-ISSN

1095-953X

Volume

188

First Page

106332

PubMed ID

37890559

Digital Object Identifier (DOI)

10.1016/j.nbd.2023.106332

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