Lipid Metabolism in Late-Onset Alzheimer's Disease Differs from Patients Presenting with Other Dementia Phenotypes.

Syena Sarrafpour,Cora Ormseth,Alfred Fonteh,Xianghong Arakaki,Michael Harrington,Abby Chiang

doi:10.3390/ijerph16111995

Abstract

Abnormal cerebrospinal fluid (CSF) levels of β-amyloid peptides (Aβ42) and Tau and cognitive decline are typical characteristics of Alzheimer’s disease (AD). Since dysregulation in lipid metabolism accompanies abnormal amyloid formation, we quantified glycerophospholipids (GP) and sphingolipids (SP) in CSF fractions from participants with late-onset AD (LOAD, n = 29) or with Other Dementia (OD, n = 10) to determine if alterations in lipid metabolism account for pathological differences. Aβ42 and total Tau levels were determined using a sandwich ELISA. Liposomal-based fluorescent assays were used to measure phospholipase A2 (PLA2) and acid or neutral sphingomyelinase (aSMase, nSMase) activities. Supernatant fluid (SF) and nanoparticle (NP) lipids were quantified using LC-MS/MS. Although CSF Aβ42 and Tau levels are similar, phosphatidylserine (PS) in SF and ceramide (CM) levels in NP are significantly higher in OD compared with LOAD. The aSMase but not the nSMase activity is higher in OD. PLA2 activity in CSF from OD subjects positively correlates with several GP classes in SF and NP fractions but not in LOAD fractions. Our data indicate differences in CSF lipid metabolism between dementia variants. Higher levels of inflammatory and apoptotic lipids may induce faster neuronal death, resulting in the earlier cognitive decline in patients with OD phenotypes.

Highlights

Late-onset Alzheimer’s disease (LOAD) is the most common neurodegenerative disorder characterized by progressive loss of cognitive function that interferes with daily activities [1].The pathology involves neurofibrillary tangles, composed of hyperphosphorylated Tau proteins and β-amyloid (Aβ) plaques, which obstruct proper synapse function and lead to neuronal cell loss and atrophy [1]
Some participants met the criteria of LOAD (n = 29), while the rest were classified as other dementias (n = 10)
The other dementias (OD) category was composed of Dementia with Lewy Body (DLB) (n = 3), behavior variant Frontotemporal Dementia (FTD) (n = 3), and vascular or mixed dementia (n = 4)

Summary

Introduction

Late-onset Alzheimer’s disease (LOAD) is the most common neurodegenerative disorder characterized by progressive loss of cognitive function that interferes with daily activities [1]. The pathology involves neurofibrillary tangles, composed of hyperphosphorylated Tau proteins and β-amyloid (Aβ) plaques, which obstruct proper synapse function and lead to neuronal cell loss and atrophy [1]. The most significant risk factor is age: the risk doubles every five years after the age of 65, with a higher AD prevalence in females than males [2,3]. There is a strong genetic component that indicates an increase in dementia risk in individuals expressing the E4 isoform of ApoE gene [4]. ApoE modulates Aβ metabolism and transport and prevents the formation of toxic Aβ fibrils [5]. Current biomarkers of AD include elevated CSF T-Tau, elevated P-Tau, and diminished

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