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

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.

Fat and Protein Combat Triggers Immunological Weapons of Innate and Adaptive Immune Systems to Launch Neuroinflammation in Parkinson’s Disease

“…Conversely, levels of ceramides, specifically monohexosylceramides, were found to be elevated in PD patients with GBA mutations. Accordingly, higher ceramide levels have been observed in the plasma, primary visual cortex, and CSF of PD patients [168,[173][174][175]. This trend has also been observed in mice models of Lrrk2 and PINK1 [176,177].…”

“…Elevated levels of SM and cerebrosides have been observed in substantia nigra of male PD patients [179]. Interestingly, SM was also observed to be lower in the ACC of PD [168] patients and the CSF of AD patients [174]. SM treatment of SK-N-SH neuronal cells increased the expression of α-syn.…”

Genetic Inactivation of Free Fatty Acid Receptor 3 Impedes Behavioral Deficits and Pathological Hallmarks in the APPswe Alzheimer’s Disease Mouse Model

“…Despite these efforts, current therapies for AD can only temporarily improve symptoms of memory loss without delaying the course of the disease—i.e., the death of neurons and the decline in higher cognitive functions [ 51 ]. Growing evidence demonstrates that defects in lipid metabolism and, consequently, alterations in vesicular dynamics and synaptic plasticity are related to the pathogenesis of AD [ 4 , 5 ]. Recently, it has been demonstrated that the plasma lipidome is dysregulated in AD.…”

“…Alzheimer’s disease (AD) is a neurodegenerative disorder among the elderly, characterized by progressive deterioration of cognition, with a complex etiology involving multiple processes [ 1 ] Neuropathological features include senile plaques (SP) composed of aggregated amyloid β peptides (Aβ) derived from aberrant processing of the amyloid precursor protein (APP), neurofibrillary tangles (NFT) composed of hyperphosphorylated tau protein, and synaptic and neuronal loss [ 2 ]. In light of many recent studies, defects in lipid metabolism and consequent alterations in the membrane concentration of phospholipids may impact the development of pathophysiological features of AD [ 3 , 4 , 5 , 6 , 7 , 8 ]. In fact, the formation of SP and NFT correlates with decreased phospholipid biosynthesis and increased lipid degradation or peroxidation [ 9 , 10 ] that contribute to synaptic impairment and neuronal loss [ 11 ].…”

Genetic Inactivation of Free Fatty Acid Receptor 3 Impedes Behavioral Deficits and Pathological Hallmarks in the APP Swe Alzheimer’s Disease Mouse Model

“…Neuropathological features include senile plaques (SP), composed of aggregated amyloid β peptides (Aβ) derived from aberrant processing of the amyloid precursor protein (APP), neuro brillary tangles (NFT), composed of hyperphosphorylated tau protein, and synaptic and neuronal loss [2]. In light of many recent studies, defects in lipid metabolism and consequent alterations in the membrane concentration of phospholipids may impact the development of pathophysiological features of AD [3][4][5][6][7][8]. In fact, the formation of SP and NFT correlates with decreased phospholipid biosynthesis and increased lipid degradation or peroxidation [9,10] that contribute to synaptic impairment and neuronal loss [11].…”