阿尔茨海默病(AD)进展的主要特征是神经肽生长抑素(SST)水平的改变,和SST阳性中间神经元(SST-INs)与淀粉样β斑块的共定位,导致细胞死亡。在这篇理论综述中,我提出了一种基于SST-IN功能减退和活动过度的AD发病机制的分子模型。即,功能低下和过度活跃的SST-INs在早期阶段努力控制内侧区域的过度活跃,通过过度的突触前GABAB抑制导致轴突Aβ的产生,GABAB1a/APP复合物下调和内在化。同时,过量的SST-14释放以淀粉样蛋白的形式积累在SST-INs附近,与Aβ结合形成毒性混合低聚物。这导致通过兴奋性毒性的SST-IN死亡差异,进一步解除抑制,SST赤字,Aβ释放增加,纤颤和斑块形成。Aβ斑块,因此,过度活跃的网络和SST-IN分布在大脑中紧密重叠。相反,过度活跃的SST-INs对突触后SST2/4对gulutamater能神经元的慢性刺激可促进强烈的丝裂原活化蛋白激酶(MAPK)p38活性,导致体树突状p-tau染色和细胞凋亡/神经变性-与p38和神经原纤维缠结之间几乎完全重叠一致。该模型适用于解释AD进展的一些主要危险因素和标志物。包括线粒体功能障碍,APOE4基因型,性别依赖的脆弱性,过度活跃的神经胶质细胞,营养不良性神经突,突触/脊柱丢失,除其他外。最后,该模型还可以揭示AD神经心理学的定性方面,特别是在空间和声明性领域(情景,语义)记忆,在上下文不歧视的叠加模式下,合奏不稳定,干扰和概括。
Among the central features of Alzheimer\'s disease (AD) progression are altered levels of the neuropeptide somatostatin (SST), and the colocalisation of SST-positive interneurons (SST-INs) with amyloid-β plaques, leading to cell death. In this theoretical review, I propose a molecular model for the pathogenesis of AD based on SST-IN hypofunction and hyperactivity. Namely, hypofunctional and hyperactive SST-INs struggle to control hyperactivity in medial regions in early stages, leading to axonal Aβ production through excessive presynaptic GABAB inhibition, GABAB1a/APP complex downregulation and internalisation. Concomitantly, excessive SST-14 release accumulates near SST-INs in the form of amyloids, which bind to Aβ to form toxic mixed oligomers. This leads to differential SST-IN death through excitotoxicity, further disinhibition, SST deficits, and increased Aβ release, fibrillation and plaque formation. Aβ plaques, hyperactive networks and SST-IN distributions thereby tightly overlap in the brain. Conversely, chronic stimulation of postsynaptic SST2/4 on gulutamatergic neurons by hyperactive SST-INs promotes intense Mitogen-Activated Protein Kinase (MAPK) p38 activity, leading to somatodendritic p-tau staining and apoptosis/neurodegeneration - in agreement with a near complete overlap between p38 and neurofibrillary tangles. This model is suitable to explain some of the principal risk factors and markers of AD progression, including mitochondrial dysfunction, APOE4 genotype, sex-dependent vulnerability, overactive glial cells, dystrophic neurites, synaptic/spine losses, inter alia. Finally, the model can also shed light on qualitative aspects of AD neuropsychology, especially within the domains of spatial and declarative (episodic, semantic) memory, under an overlying pattern of contextual indiscrimination, ensemble instability, interference and generalisation.