Reactive astrogliosis accompanies the two neuropathological hallmarks of Alzheimer’s disease (AD)—Aβ plaques and neurofibrillary tangles—and parallels neurodegeneration in AD and AD-related dementias (ADRD). Thus, there is growing interest in developing imaging and fluid biomarkers of reactive astrogliosis for AD/ADRD diagnosis and prognostication. Monoamine oxidase-B (MAO-B) is emerging as a target for PET imaging radiotracers of reactive astrogliosis. However, a thorough characterization of MAO-B expression in postmortem control and AD/ADRD brains is lacking. We sought to: (1) identify the primary cell type(s) expressing MAO-B in control and AD brains; (2) quantify MAO-B immunoreactivity in multiple brain regions of control and AD donors as a proxy for PET radiotracer uptake; (3) correlate MAO-B level with local AD neuropathological changes, reactive glia, and cortical atrophy; (4) determine whether the MAOB rs1799836 SNP genotype impacts MAO-B expression level; (5) compare MAO-B immunoreactivity across AD/ADRD, including Lewy body diseases (LBD) and frontotemporal lobar degenerations with tau (FTLD-Tau) and TDP-43 (FTLD-TDP). We found that MAO-B is mainly expressed by subpial and perivascular cortical astrocytes as well as by fibrous white matter astrocytes in control brains, whereas in AD brains, MAO-B is significantly upregulated by both cortical reactive astrocytes and white matter astrocytes across temporal, frontal, and occipital lobes. By contrast, MAO-B expression level was unchanged and lowest in cerebellum. Cortical MAO-B expression was independently associated with cortical atrophy and local measures of reactive astrocytes and microglia, and significantly increased in reactive astrocytes surrounding Thioflavin-S+ dense-core Aβ plaques. MAO-B expression was not affected by the MAOB rs1799836 SNP genotype. MAO-B expression was also significantly increased in the frontal cortex and white matter of donors with corticobasal degeneration, Pick’s disease, and FTLD-TDP, but not in LBD or progressive supranuclear palsy. These findings support ongoing efforts to develop MAO-B-based PET radiotracers to image reactive astrogliosis in AD/ADRD.

反应性星形胶质细胞增生伴随着阿尔茨海默病 (AD) 的两个神经病理学特征——Aβ 斑块和神经原纤维缠结，并且与 AD 和 AD 相关痴呆 (ADRD) 中的神经退行性病变相似。因此，人们对开发用于 AD/ADRD 诊断和预测的反应性星形胶质细胞增生的成像和液体生物标志物越来越感兴趣。单胺氧化酶-B (MAO-B) 正在成为反应性星形胶质细胞增生 PET 成像放射性示踪剂的靶标。然而，缺乏对死后对照和 AD/ADRD 大脑中 MAO-B 表达的全面表征。我们试图：（1）确定对照和 AD 大脑中表达 MAO-B 的主要细胞类型； (2) 量化对照和 AD 供体多个脑区的 MAO-B 免疫反应性，作为 PET 放射性示踪剂摄取的代表； (3) 将 MAO-B 水平与局部 AD 神经病理变化、反应性神经胶质细胞和皮质萎缩相关联； (4)确定MAOB rs1799836 SNP基因型是否影响MAO-B表达水平； (5) 比较 AD/ADRD 中的 MAO-B 免疫反应性，包括路易体病 (LBD) 和 tau 蛋白 (FTLD-Tau) 和 TDP-43 (FTLD-TDP) 额颞叶变性。我们发现 MAO-B 主要由软膜下和血管周围皮质星形胶质细胞以及对照大脑中的纤维白质星形胶质细胞表达，而在 AD 大脑中，MAO-B 被皮质反应性星形胶质细胞和跨颞叶白质星形胶质细胞显着上调。额叶和枕叶。相比之下，MAO-B 表达水平没有变化，并且在小脑中最低。皮质 MAO-B 表达与皮质萎缩以及反应性星形胶质细胞和小胶质细胞的局部测量独立相关，并且硫磺素-S+ 致密核心 Aβ 斑块周围的反应性星形胶质细胞显着增加。 MAO-B 表达不受MAOB rs1799836 SNP 基因型的影响。在患有皮质基底节变性、皮克氏病和 FTLD-TDP 的供体中，MAO-B 表达在额叶皮质和白质中也显着增加，但在 LBD 或进行性核上性麻痹中则没有。这些发现支持目前开发基于 MAO-B 的 PET 放射性示踪剂的努力，以对 AD/ADRD 中的反应性星形胶质细胞增生进行成像。