Polyunsaturated Fatty Acid Composition of Cerebrospinal Fluid Fractions Shows Their Contribution to Cognitive Resilience of a Pre-symptomatic Alzheimer's Disease Cohort
Polyunsaturated Fatty Acid Composition of Cerebrospinal Fluid Fractions Shows Their Contribution to Cognitive Resilience of a Pre-symptomatic Alzheimer's Disease Cohort
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DOI：
10.3389/fphys.2020.00083
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发表时间：
2020-02-14
影响因子：
4
通讯作者：
Harrington, Michael G.
中科院分区：
文献类型：
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作者：
Fonteh, Alfred N.;Cipolla, Matthew;Harrington, Michael G.
阿尔茨海默病（AD）的病理特征是早期和长期的淀粉样肽（A β）水平下降，并伴随脑脊液（CSF）中磷酸化tau浓度的增加。我们认为脂质代谢的变化可能导致AD中A β(42)的异常加工。我们的目的是确定多不饱和脂肪酸（PUFA）代谢是否可以区分症状前AD、正常衰老AD和症状性AD。利用神经心理学测量和脑脊液（CSF） A β (42)/T-tau，我们将老年研究参与者分为三组：认知健康正常A β (42)/T-tau (CH-NAT)，认知健康病理A β (42)/T-tau （CH-PAT）和AD个体。我们利用光散射测定脑脊液颗粒的大小分布和浓度，并利用气相色谱结合质谱测定纳米颗粒（NP）部分、上清液（SF）中PUFA的组成，以及未酯化PUFA的水平。与CH-NAT相比，4种PUFAs （C20:2n-6、C20:3n-3、C22:4n-6、C22:5n-3）在AD的NP中富集。与CH-PAT相比，AD的NP分数中C20:3n-3水平较高。当归一化到脑脊液中NPs的数量时，与AD相比，CH-NAT和CH-PAT的PUFA水平显著高于AD。在SF中，只有二十二碳六烯酸（DHA, C22:6n-3）的水平区分了所有三个临床组。与其他临床组相比，CH-NAT组的未酯化DHA含量也较高。我们的研究还表明，CH参与者的NP PUFAs与CSF A β呈负相关（42），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A β(42)或T-tau相关的不同脑脊液中PUFAs的谱不同。这些研究表明PUFA代谢与淀粉样蛋白和tau蛋白加工有关。重要的是，在认知健康且A β (42)/T-tau异常的研究参与者中，较高的PUFA水平表明PUFA增强了症状前AD人群的认知恢复能力。我们提出，预防大脑PUFA消耗的干预措施可能通过稳定A β(42)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，将揭示新的生物标志物和潜在的预防方法。
Alzheimer's disease (AD) pathology is characterized by an early and prolonged decrease in the amyloid peptide (A beta) 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 A beta(42) 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 A beta(42)/T-tau in cerebrospinal fluid (CSF), we classify three groups of elderly study participants: cognitively healthy with normal A beta(42)/T-tau (CH-NAT), cognitively healthy with pathological A beta(42)/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 A beta(42) 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 A beta(42) 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 A beta(42)/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 A beta(42) 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.