Power Saige K, Venkatesan Sridevi, Qu Sarah, McLaurin JoAnne, Lambe Evelyn K
Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada.
Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada.
Transl Neurodegener. 2024 Dec 3;13(1):58. doi: 10.1186/s40035-024-00452-7.
Cognitive reserve allows for resilience to neuropathology, potentially through active compensation. Here, we examine ex vivo electrophysiological evidence for active compensation in Alzheimer's disease (AD) focusing on the cholinergic innervation of layer 6 in prefrontal cortex. Cholinergic pathways are vulnerable to neuropathology in AD and its preclinical models, and their modulation of deep layer prefrontal cortex is essential for attention and executive function.
We functionally interrogated cholinergic modulation of prefrontal layer 6 pyramidal neurons in two preclinical models: a compound transgenic AD mouse model that permits optogenetically-triggered release of endogenous acetylcholine and a transgenic AD rat model that closely recapitulates the human trajectory of AD. We then tested the impact of therapeutic interventions to further amplify the compensated responses and preserve the typical kinetic profile of cholinergic signaling.
In two AD models, we found potentially compensatory upregulation of functional cholinergic responses above non-transgenic controls after onset of pathology. To identify the locus of this enhanced cholinergic signal, we dissected key pre- and post-synaptic components with pharmacological strategies. We identified a significant and selective increase in post-synaptic nicotinic receptor signalling on prefrontal cortical neurons. To probe the additional impact of therapeutic intervention on the adapted circuit, we tested cholinergic and nicotinic-selective pro-cognitive treatments. Inhibition of acetylcholinesterase further enhanced endogenous cholinergic responses but greatly distorted their kinetics. Positive allosteric modulation of nicotinic receptors, by contrast, enhanced endogenous cholinergic responses and retained their rapid kinetics.
We demonstrate that functional nicotinic upregulation occurs within the prefrontal cortex in two AD models. Promisingly, this nicotinic signal can be further enhanced while preserving its rapid kinetic signature. Taken together, our work suggests that compensatory mechanisms are active within the prefrontal cortex that can be harnessed by nicotinic receptor positive allosteric modulation, highlighting a new direction for cognitive treatment in AD neuropathology.
认知储备可能通过积极补偿机制使人对神经病理学具有恢复力。在此，我们研究了阿尔茨海默病（AD）中积极补偿的离体电生理证据，重点关注前额叶皮层第6层的胆碱能神经支配。胆碱能通路在AD及其临床前模型中易受神经病理学影响，其对前额叶皮层深层的调节对注意力和执行功能至关重要。
我们在两种临床前模型中对前额叶第6层锥体神经元的胆碱能调节进行了功能研究：一种复合转基因AD小鼠模型，可通过光遗传学触发内源性乙酰胆碱释放；以及一种转基因AD大鼠模型，该模型能紧密模拟人类AD病程。然后，我们测试了治疗干预措施的影响，以进一步增强补偿反应并保留胆碱能信号的典型动力学特征。
在两种AD模型中，我们发现病理发作后功能性胆碱能反应相对于非转基因对照有潜在的补偿性上调。为了确定这种增强的胆碱能信号的位点，我们采用药理学策略剖析了关键的突触前和突触后成分。我们发现前额叶皮层神经元上突触后烟碱型受体信号有显著且选择性的增加。为了探究治疗干预对适应性回路的额外影响，我们测试了胆碱能和烟碱型选择性促认知治疗。乙酰胆碱酯酶抑制进一步增强了内源性胆碱能反应，但极大地扭曲了其动力学。相比之下，烟碱型受体的正向变构调节增强了内源性胆碱能反应并保留了其快速动力学。
我们证明在两种AD模型中前额叶皮层内发生了功能性烟碱型上调。有希望的是，这种烟碱型信号可以在保留其快速动力学特征的同时进一步增强。综上所述，我们的工作表明前额叶皮层内存在活跃的补偿机制，可通过烟碱型受体正向变构调节加以利用，为AD神经病理学的认知治疗指明了新方向。
