Accumulation of Cerebrospinal Fluid Glycerophospholipids and Sphingolipids in Cognitively Healthy Participants With Alzheimer's Biomarkers Precedes Lipolysis in the Dementia Stage.

Alfred N Fonteh,Abby J Chiang,Michael G Harrington,Sarah P Edminster,Xianghong Arakaki

doi:10.3389/fnins.2020.611393

Alfred N Fonteh, Abby J Chiang + Show 3 more

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https://doi.org/10.3389/fnins.2020.611393

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Abstract

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 Aβ42/Tau levels established biomarkers of AD, we define a subset of CH participants with normal Aβ42/Tau (CH-NAT) and another group with abnormal or pathological Aβ42/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 (Aβ) 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.

Highlights

Specific mutations lead inevitably to familial Alzheimer’s disease (FAD; Lacour et al, 2019; Wong et al, 2020), and gene polymorphisms are associated with late-onset Alzheimer’s disease (AD; Morelli et al, 1996; Casadei et al, 1999; Dursun et al, 2008; Du et al, 2016; Zuin et al, 2020), the most common form of AD
These results suggest that the changes mentioned above in GPs and SPs in biochemical and dementia stages likely result from the brain pathophysiology
The study participants who are CH with pathological CSF Aβ42/tau have been recently confirmed to be at higher risk for a cognitive decline when we found 11/28 (40%, p < 0.0001) of this CH-PAT group declined cognitively with an AD pattern after 4 years, while none of the CH-NAT group had measurable decline (Harrington et al, 2019)

Summary

Introduction

Specific mutations lead inevitably to familial Alzheimer’s disease (FAD; Lacour et al, 2019; Wong et al, 2020), and gene polymorphisms are associated with late-onset Alzheimer’s disease (AD; Morelli et al, 1996; Casadei et al, 1999; Dursun et al, 2008; Du et al, 2016; Zuin et al, 2020), the most common form of AD Some risk factors such as age, education, apolipoprotein ε4 (ApoE-4), hypertension, diabetes, hyperlipidemia, obesity, smoking, and head trauma have been identified, but none is necessary or sufficient to cause AD (Devanand et al, 2013; Guimas Almeida et al, 2018; Takahashi et al, 2018). Since Aβ42 derives from the transmembrane APP, clues to the mechanism that links these multiple risk factors to the Aβ42 cascade may, be revealed in the neuronal membrane environment at the earliest pathology stage of AD

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