Fonteh Alfred N, Cipolla Matthew, Chiang Abby J, Edminster Sarah P, Arakaki Xianghong, Harrington Michael G
Neurosciences, Huntington Medical Research Institutes, Pasadena, CA, United States.
Front Physiol. 2020 Feb 14;11:83. doi: 10.3389/fphys.2020.00083. eCollection 2020.
Alzheimer's disease (AD) pathology is characterized by an early and prolonged decrease in the amyloid peptide (Aβ) levels concomitant with a later increase in phospho-tau concentrations in cerebrospinal fluid (CSF). We propose that changes in lipid metabolism can contribute to the abnormal processing of Aβ in AD. Our aim was to determine if polyunsaturated fatty acid (PUFA) metabolism can differentiate pre-symptomatic AD from normal aging and symptomatic AD. Using neuropsychology measures and Aβ/T-tau in cerebrospinal fluid (CSF), we classify three groups of elderly study participants: cognitively healthy with normal Aβ/T-tau (CH-NAT), cognitively healthy with pathological Aβ/T-tau (CH-PAT), and AD individuals. We determined the size distribution and the concentration of CSF particles using light scattering and quantified PUFA composition in the nanoparticulate (NP) fraction, supernatant fluid (SF), and unesterified PUFA levels using gas chromatography combined with mass spectrometry. Four PUFAs (C20:2n-6, C20:3n-3, C22:4n-6, C22:5n-3) were enriched in NP of AD compared with CH-NAT. C20:3n-3 levels were higher in the NP fraction from AD compared with CH-PAT. When normalized to the number of NPs in CSF, PUFA levels were significantly higher in CH-NAT and CH-PAT compared with AD. In the SF fractions, only the levels of docosahexaenoic acid (DHA, C22:6n-3) differentiated all three clinical groups. Unesterified DHA was also higher in CH-NAT compared with the other clinical groups. Our studies also show that NP PUFAs in CH participants negatively correlate with CSF Aβ while C20:4n-6, DHA, and n-3 PUFAs in the SF fraction positively correlate with T-tau. The profile of PUFAs in different CSF fractions that correlate with Aβ or with T-tau are different for CH-NAT compared with CH-PAT. These studies show that PUFA metabolism is associated with amyloid and tau processing. Importantly, higher PUFA levels in the cognitively healthy study participants with abnormal Aβ/T-tau suggest that PUFA enhances the cognitive resilience of the pre-symptomatic AD population. We propose that interventions that prevent PUFA depletion in the brain may prevent AD pathology by stabilizing Aβ and tau metabolism. Further studies to determine changes in PUFA composition during the progression from pre-symptomatic to AD should reveal novel biomarkers and potential preventive approaches.
阿尔茨海默病（AD）的病理特征是脑脊液（CSF）中淀粉样肽（Aβ）水平早期且持续下降，同时磷酸化tau浓度后期升高。我们认为脂质代谢的变化可能导致AD中Aβ的异常加工。我们的目的是确定多不饱和脂肪酸（PUFA）代谢是否能区分症状前AD与正常衰老及症状性AD。通过神经心理学测量和脑脊液中的Aβ/T-tau，我们将三组老年研究参与者进行分类：Aβ/T-tau正常的认知健康者（CH-NAT）、Aβ/T-tau病理性的认知健康者（CH-PAT）以及AD患者。我们使用光散射测定脑脊液颗粒的大小分布和浓度，并通过气相色谱-质谱联用技术对纳米颗粒（NP）部分、上清液（SF）中的PUFA组成以及游离PUFA水平进行定量。与CH-NAT相比，AD的NP中富集了四种PUFA（C20:2n-6、C20:3n-3、C22:4n-6、C22:5n-3）。与CH-PAT相比，AD的NP部分中C20:3n-3水平更高。当以脑脊液中NP的数量进行标准化时，CH-NAT和CH-PAT中的PUFA水平显著高于AD。在SF部分，只有二十二碳六烯酸（DHA，C22:6n-3）水平能区分所有三个临床组。与其他临床组相比，CH-NAT中的游离DHA也更高。我们的研究还表明，CH参与者中的NP PUFAs与脑脊液Aβ呈负相关，而SF部分中的C20:4n-6、DHA和n-3 PUFAs与T-tau呈正相关。与CH-PAT相比，CH-NAT中与Aβ或T-tau相关的不同脑脊液部分的PUFA谱不同。这些研究表明PUFA代谢与淀粉样蛋白和tau加工有关。重要的是，Aβ/T-tau异常的认知健康研究参与者中较高的PUFA水平表明PUFA增强了症状前AD人群的认知恢复力。我们认为，防止大脑中PUFA消耗的干预措施可能通过稳定Aβ和tau代谢来预防AD病理。进一步研究确定从症状前到AD进展过程中PUFA组成的变化，应能揭示新的生物标志物和潜在的预防方法。
