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.
Complex Adaptive Systems Initiative, Arizona State University, Tempe, AZ, USA; Institute for Future Health, Scottsdale, AZ, USA.
Neurobiol Dis. 2023 Nov;188:106332. doi: 10.1016/j.nbd.2023.106332. Epub 2023 Oct 26.
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.
唐氏综合征（DS）是一种由人类 21 号染色体三体引起的遗传疾病。除了智力障碍外，DS 还表现为早衰表型和阿尔茨海默病（AD）神经病理学，包括隔-海马回路易损性和基底前脑胆碱能神经元（BFCNs）的退化。Ts65Dn 小鼠模型再现了 DS/AD 病理学的关键方面，即 BFCNs 的年龄相关萎缩和隔-海马依赖行为任务中的认知能力下降。我们研究了母体胆碱补充（MCS），一种耐受良好的治疗方式，是否可以保护易损的 BFCNs 免受三体后代与年龄和基因型相关的退化。我们还研究了三体和 MCS 对 GABA 能基底前脑钙蛋白神经元（BFPNs）的影响，这是该 DS 模型中未探索的神经元群体。使用 Ts65Dn 小鼠和二倍体（2N）同窝仔鼠的内侧隔核和斜角带垂直支（MSN/VDB）的共聚焦 z 堆栈，对胆碱乙酰转移酶（ChAT）免疫反应性 BFCNs 和钙蛋白免疫反应性 BFPNs 进行了无偏立体学分析，分别在 3-4 个月和 10-12 个月龄时。与未补充的对照组相比，MCS 三体后代的 ChAT 免疫反应性神经元数量和密度显著增加，MSN/VDB 中 ChAT 免疫反应性神经突的面积也增加。MCS 还挽救了 Ts65Dn 后代的 BFPN 数量和密度，这是对非胆碱能细胞群体的一种新的挽救。此外，MCS 防止了 2N 后代 BFCNs 和 MSN/VDB 区域面积的年龄相关丧失，表明存在与基因型无关的神经保护益处。这些发现表明，MCS 为易损的 BFCNs 和非胆碱能隔-海马 BFPNs 提供了神经保护，表明这种方式具有作为 DS 生命早期治疗的转化价值，并将益处扩展到整个老年人群。
