RESUMO
Insight into lipids' roles in Alzheimer's disease (AD) pathophysiology is limited because brain membrane lipids have not been characterized in cognitively healthy (CH) individuals. Since age is a significant risk factor of AD, we hypothesize that aging renders the amyloid precursor protein (APP) more susceptible to abnormal processing because of deteriorating membrane lipids. To reflect brain membranes, we studied their lipid components in cerebrospinal fluid (CSF) and brain-derived CSF nanoparticle membranes. Based on CSF Aß42/Tau levels established biomarkers of AD, we define a subset of CH participants with normal Aß42/Tau (CH-NAT) and another group with abnormal or pathological Aß42/Tau (CH-PAT). We report that glycerophospholipids are differentially metabolized in the CSF supernatant fluid and nanoparticle membrane fractions from CH-NAT, CH-PAT, and AD participants. Phosphatidylcholine molecular species from the supernatant fraction of CH-PAT were higher than in the CH-NAT and AD participants. Sphingomyelin levels in the supernatant fraction were lower in the CH-PAT and AD than in the CH-NAT group. The decrease in sphingomyelin corresponded with an increase in ceramide and dihydroceramide and an increase in the ceramide to sphingomyelin ratio in AD. In contrast to the supernatant fraction, sphingomyelin is higher in the nanoparticle fraction from the CH-PAT group, accompanied by lower ceramide and dihydroceramide and a decrease in the ratio of ceramide to sphingomyelin in CH-PAT compared with CH-NAT. On investigating the mechanism for the lipid changes in AD, we observed that phospholipase A2 (PLA2) activity was higher in the AD group than the CH groups. Paradoxically, acid and neutral sphingomyelinase (SMase) activities were lower in AD compared to the CH groups. Considering external influences on lipids, the clinical groups did not differ in their fasting blood lipids or dietary lipids, consistent with the CSF lipid changes originating from brain pathophysiology. The lipid accumulation in a prodromal AD biomarker positive stage identifies perturbation of lipid metabolism and disturbances in APP/Amyloid beta (Aß) as early events in AD pathophysiology. Our results identify increased lipid turnover in CH participants with AD biomarkers, switching to a predominantly lipolytic state in dementia. This knowledge may be useful for targeting and testing new AD treatments.
RESUMO
Alzheimer's disease (AD) pathology is characterized by an early and prolonged decrease in the amyloid peptide (Aß) 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 Aß42 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 Aß42/T-tau in cerebrospinal fluid (CSF), we classify three groups of elderly study participants: cognitively healthy with normal Aß42/T-tau (CH-NAT), cognitively healthy with pathological Aß42/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 Aß42 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 Aß42 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 Aß42/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 Aß42 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.