Fletcher Rachel, Hoppe Meagan, McQuail Joseph A, Hernandez Caesar M, Hernandez Abbi R
University of Florida, Gainesville, FL, USA.
Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA.
Mol Neurobiol. 2025 Apr 29. doi: 10.1007/s12035-025-04988-1.
Impaired cognitive function is a hallmark of advancing age, and the potential to reverse or delay these cognitive deficits through dietary intervention holds promise for improving quality of life for older adults. Specifically, ketogenic diets (KDs) have now been widely used for the treatment of several neurological and peripheral disorders, including diseases profoundly affecting cognitive health, of which advanced age is the single greatest risk factor. However, the precise mechanisms of the efficacy of KD-based interventions to reverse age-related cognitive and neurobiological declines are not fully elucidated. We have previously demonstrated that a KD improves cognitive function, with concurrent increases in global levels of proteins related to synaptic signaling in the aging hippocampus (HPC) and prefrontal cortex (PFC). Despite these advances, it remains unclear as to whether these changes reflect biochemical modifications specifically localized to synaptic terminals. To address this important, unanswered question, we purified synaptosomes from the HPC and PFC of aging rats fed a KD or control diet (CD) for a minimum of 4 months and quantified 10 proteins related to synaptic transmission. In contrast to previous studies of global protein expression, the signaling proteins measured did not show significant differences between diet groups in synaptosomes isolated from either region. When pre-mortem performance on an Object-Place Paired Association task was considered, we found a significant correlation between several proteins within the HPC and PFC synaptosomes of CD-fed rats, more pronounced in CD-fed aged rats, that are conspicuously absent in KD-fed rats from both age groups. Moreover, there is a significant alteration in the ratio of VGAT/VGluT1, markers of excitatory and inhibitory synaptic vesicles, in the PFC with dietary intervention that is absent in the HPC, confirming prior reports of regionally specific alterations in excitatory and inhibitory signaling post KD. These new and extended findings reveal important, naturally occurring associations between protein levels localized to synaptic terminals, while clarifying that effects KD likely increase synaptic abundance without altering the biochemical composition of isolated synapses.
认知功能受损是衰老的一个标志，通过饮食干预来逆转或延缓这些认知缺陷的可能性为改善老年人的生活质量带来了希望。具体而言，生酮饮食（KDs）现已广泛用于治疗多种神经和外周疾病，包括严重影响认知健康的疾病，而高龄是其中最大的单一风险因素。然而，基于KD的干预措施逆转与年龄相关的认知和神经生物学衰退的具体机制尚未完全阐明。我们之前已经证明，KD可以改善认知功能，同时老龄海马体（HPC）和前额叶皮质（PFC）中与突触信号相关的蛋白质整体水平会增加。尽管有这些进展，但尚不清楚这些变化是否反映了特定定位于突触终末的生化修饰。为了解决这个重要的、未得到解答的问题，我们从喂食KD或对照饮食（CD）至少4个月的老龄大鼠的HPC和PFC中纯化了突触体，并对10种与突触传递相关的蛋白质进行了定量。与之前关于整体蛋白质表达的研究不同，在从这两个区域分离出的突触体中，所检测的信号蛋白在饮食组之间没有显示出显著差异。当考虑在物体-位置配对联想任务中的死前表现时，我们发现喂食CD的大鼠的HPC和PFC突触体中的几种蛋白质之间存在显著相关性，在喂食CD的老龄大鼠中更为明显，而在两个年龄组的喂食KD的大鼠中则明显不存在。此外，饮食干预后PFC中兴奋性和抑制性突触小泡标记物VGAT/VGluT1的比例有显著变化，而HPC中没有，这证实了之前关于KD后兴奋性和抑制性信号区域特异性变化的报道。这些新的和扩展的发现揭示了定位于突触终末的蛋白质水平之间重要的自然关联，同时表明KD的作用可能增加突触丰度而不改变分离突触的生化组成。
