Patel Ashay O, Caldwell Andrew B, Ramachandran Srinivasan, Subramaniam Shankar
Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA.
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
J Alzheimers Dis Rep. 2023 Aug 29;7(1):957-972. doi: 10.3233/ADR-220098. eCollection 2023.
While Alzheimer's disease (AD) pathology is associated with altered brain structure, it is not clear whether gene expression changes mirror the onset and evolution of pathology in distinct brain regions. Deciphering the mechanisms which cause the differential manifestation of the disease across different regions has the potential to help early diagnosis.
We aimed to identify common and unique endotypes and their regulation in tangle-free neurons in sporadic AD (SAD) across six brain regions: entorhinal cortex (EC), hippocampus (HC), medial temporal gyrus (MTG), posterior cingulate (PC), superior frontal gyrus (SFG), and visual cortex (VCX).
To decipher the states of tangle-free neurons across different brain regions in human subjects afflicted with AD, we performed analysis of the neural transcriptome. We explored changes in differential gene expression, functional and transcription factor target enrichment, and co-expression gene module detection analysis to discern disease-state transcriptomic variances and characterize endotypes. Additionally, we compared our results to tangled AD neuron microarray-based study and the Allen Brain Atlas.
We identified impaired neuron function in EC, MTG, PC, and VCX resulting from REST activation and reversal of mature neurons to a precursor-like state in EC, MTG, and SFG linked to SOX2 activation. Additionally, decreased neuron function and increased dedifferentiation were linked to the activation of SUZ12. Energetic deficit connected to NRF1 inactivation was found in HC, PC, and VCX.
Our findings suggest that SAD manifestation varies in scale and severity in different brain regions. We identify endotypes, such as energetic shortfalls, impaired neuronal function, and dedifferentiation.
虽然阿尔茨海默病（AD）病理与大脑结构改变有关，但尚不清楚基因表达变化是否反映了不同脑区病理的发生和演变。解读导致该疾病在不同区域出现差异表现的机制可能有助于早期诊断。
我们旨在识别散发性AD（SAD）患者六个脑区（内嗅皮质（EC）、海马体（HC）、颞中回（MTG）、后扣带回（PC）、额上回（SFG）和视觉皮质（VCX））中无缠结神经元的常见和独特内型及其调控机制。
为了解读AD患者不同脑区无缠结神经元的状态，我们进行了神经转录组分析。我们探索了差异基因表达、功能和转录因子靶点富集的变化，以及共表达基因模块检测分析，以辨别疾病状态下的转录组差异并表征内型。此外，我们将结果与基于缠结AD神经元微阵列的研究以及艾伦脑图谱进行了比较。
我们发现，REST激活导致EC、MTG、PC和VCX中神经元功能受损，而EC、MTG和SFG中成熟神经元向类似前体状态的逆转与SOX2激活有关。此外，神经元功能下降和去分化增加与SUZ12的激活有关。在HC、PC和VCX中发现了与NRF1失活相关的能量缺乏。
我们的研究结果表明，SAD在不同脑区的表现存在规模和严重程度的差异。我们识别出了内型，如能量不足、神经元功能受损和去分化。
