Fessel Jeffrey
Department of Medicine University of California, San Francisco San Francisco California USA.
Alzheimers Dement (N Y). 2021 Feb 5;7(1):e12126. doi: 10.1002/trc2.12126. eCollection 2021.
Prevention is better than cure and prevention of Alzheimer's disease (AD) may be possible. In elderly persons who are cognitively normal, synaptic hypometabolism as shown by reduced cerebral uptake of fluorodeoxyglucose (F-FDG), provides a premonitory signal of potential, future loss of cognition if those individuals also have present evidence of amyloid deposition seen in the Pittsburgh compound B positron emission tomography (PIB-PET) scan for amyloid. Those are the persons who should be targeted if one aims to prevent AD. The synaptic hypometabolism implies that the brain's availability of adenosine triphosphate (ATP) is inadequate for performance of all required synaptic functions. This review first describes the basis for asserting that reduced cerebral uptake of F-FDG accurately reflects synaptic hypometabolism; second, explains the basis for asserting that hypometabolism implies inadequate ATP; third, shows that amyloid beta (Aβ) itself, Aβ modified by pyroglutamate to become a molecule termed pE(3)Aβ, and cyclophilin-D, in concert are the main contributors to inadequate synaptic ATP and that, therefore, reducing all of their levels would neutralize their combined effect and correct the hypometabolism. pE(3)Aβ is more neurotoxic than unmodified Aβ; and cyclophilin D inhibits ATP synthase and reduces ATP formation. Finally, this review describes an mRNA self-replicating vaccine that will raise brain levels of ATP by reducing Aβ, pyroglutamate-modified Aβ, and cyclophilin-D, and thereby-in cognitively normal elderly persons who have synaptic hypometabolism-prevent initiation of the process that terminates in AD.
预防胜于治疗，阿尔茨海默病（AD）或许可以预防。在认知正常的老年人中，脑氟脱氧葡萄糖（F-FDG）摄取减少所显示的突触代谢减退，是未来认知功能可能丧失的先兆信号，前提是这些个体在匹兹堡化合物B正电子发射断层扫描（PIB-PET）淀粉样蛋白成像中也有淀粉样蛋白沉积的证据。如果旨在预防AD，这些人就是目标人群。突触代谢减退意味着大脑中三磷酸腺苷（ATP）的可用性不足以支持所有必需的突触功能。本综述首先描述了断言脑F-FDG摄取减少准确反映突触代谢减退的依据；其次，解释了断言代谢减退意味着ATP不足的依据；第三，表明β淀粉样蛋白（Aβ）本身、焦谷氨酸修饰后成为pE(3)Aβ分子的Aβ以及亲环蛋白-D共同作用，是突触ATP不足的主要原因，因此，降低它们的所有水平将抵消其综合作用并纠正代谢减退。pE(3)Aβ比未修饰的Aβ具有更强的神经毒性；亲环蛋白D抑制ATP合酶并减少ATP生成。最后，本综述描述了一种mRNA自我复制疫苗，该疫苗将通过降低Aβ、焦谷氨酸修饰的Aβ和亲环蛋白-D来提高大脑ATP水平，从而在有突触代谢减退的认知正常老年人中预防导致AD的进程启动。
