Baghel Brijesh, Kumari Bindu, Bhattacharjee Anindita, Sharma Shiru, Roy Prasun K
School of Bio-Medical Engineering, Indian Institute of Technology (B.H.U.), Varanasi, 221005 India.
R-206, Department of Life Sciences, Shiv Nadar University (SNU), NH-91, Delhi NCR, 201314 India.
3 Biotech. 2025 May;15(5):138. doi: 10.1007/s13205-025-04264-y. Epub 2025 Apr 22.
We elucidate that the cerebellum displays striking resilience to neurodegenerative changes under aging or Alzheimer's disease (AD). We identify the neurobiological factors that underlie the natural neuroprotective characteristic of cerebellum, thereby obtaining innovative therapeutic directions that may duplicate this naturalistic neurorestorative response. We investigated the mass spectrometry/liquid chromatography-based proteomics profile from AD tissue: sparely affected cerebellum and highly affected hippocampus/cingulate/entorhinal cortex. We found 83 upregulated and 37 downregulated cerebellar genes. Top five upregulated genes were (hub-gene), these encode for neurorestorative processes, as axonal, dendritic, and myelination growth. Contrastingly, the top five downregulated genes were (hub-gene), . These encode for NADH-dehydrogenase subunit in mitochondria; their increased expression relates to mitochondrial-based ROS stress-based apoptosis; hence, their downregulation reduces apoptosis, reinforcing neural survival. Indeed, cerebellum displays unique neuroprotection, by coupling of two reciprocal cytometabolic fluxes: (1) hyperactivation of neural anabolic processing, as neuronal growth, and (2) hypoactivation of neural catabolic processing, as mitochondrial caspase-induced neural degradation. Hence, for inducing the endogenous neuroprotective response, one needs to pharmacologically modulate both these cytometabolic processes: (i) agonism of neural synaptotropic anabolic pathway, coupled to (ii) antagonism of mitochondrial catabolic neurotoxic pathway. We also observed that synaptic efficiency-encoding genes constitute majority (70%) of upregulated cerebellar genes. We noted the unexpected observations, namely that (a) the neuron is the most pivotal factor for the restorative response than any type of glial or other cells, (b) with respect to the neuron, the synaptogenesis process is much more critical than the neurogenesis process, and (c) collaterally, the hypomodulation of the mitochondrial NADHD ubiquinone activity is the key factor. A unique significance is that a naturally occurring neurorestorative response may be therapeutically harnessed in neurons, minimizing off-target effects that are often hazardous disadvantages of conventional dementia therapeutics.
The online version contains supplementary material available at 10.1007/s13205-025-04264-y.
我们阐明，小脑在衰老或阿尔茨海默病（AD）情况下对神经退行性变化表现出显著的恢复力。我们确定了小脑天然神经保护特性背后的神经生物学因素，从而获得了可能复制这种自然神经修复反应的创新治疗方向。我们研究了基于质谱/液相色谱的AD组织蛋白质组学图谱：受影响较小的小脑以及受影响严重的海马体/扣带回/内嗅皮质。我们发现83个小脑基因上调，37个小脑基因下调。上调的前五个基因（核心基因）编码神经修复过程，如轴突、树突和髓鞘生长。相反，下调的前五个基因（核心基因）编码线粒体中的NADH脱氢酶亚基；它们的表达增加与基于线粒体的活性氧应激诱导的细胞凋亡有关；因此，它们的下调减少了细胞凋亡，增强了神经存活。实际上，小脑通过两种相互的细胞代谢通量耦合表现出独特的神经保护作用：（1）神经合成代谢过程的过度激活，如神经元生长，以及（2）神经分解代谢过程的低激活，如线粒体半胱天冬酶诱导的神经降解。因此，为了诱导内源性神经保护反应，需要从药理学上调节这两种细胞代谢过程：（i）神经突触促合成代谢途径的激动作用，与（ii）线粒体分解代谢神经毒性途径的拮抗作用相结合。我们还观察到，编码突触效率的基因占上调的小脑基因的大多数（70%）。我们注意到一些意外的观察结果，即（a）神经元是恢复反应中比任何类型的神经胶质细胞或其他细胞更关键的因素，（b）就神经元而言，突触形成过程比神经发生过程更关键，以及（c）附带地，线粒体NADHD泛醌活性的低调节是关键因素。一个独特之处在于，自然发生的神经修复反应可以在神经元中进行治疗性利用，最大限度地减少传统痴呆症治疗中经常存在的有害副作用的脱靶效应。
在线版本包含可在10.1007/s13205-025-04264-y获取的补充材料。
