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

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.

Keywords: Tau proteins; amyloid; ceramide; cerebrospinal fluid; late-onset Alzheimer’s disease; lysophosphatidylcholine; other dementia; phosphatidylserine; phospholipase A2; sphingomyelinase.

Figure 1

Correlations between PLA₂ activity and GPs- LOAD demonstrated no significant correlation between PLA₂ activity and PC in NP (a). However, PLA₂ positively correlated with PC in NP in OD samples (ρ = 0.81, p < 0.03) (b). PLA₂ activity in CSF from LOAD subjects did not correlate with NP LPC/PC (c), while PLA₂ activity of OD negatively correlated (ρ = −0.88, p < 0.01) with NP LPC/PC (d). LOAD PLA₂ activity did not correlate with NP PAF (e), while OD PLA₂ activity negatively correlated (ρ = −0.74, p < 0.05) with NP PAF (f). PLA₂ activity negatively correlated with NAPE in both LOAD (ρ = −0.47, p < 0.05) (g) and OD (ρ = −0.47, p < 0.05) (h). PLA₂ activity was available for eight OD because of CSF limitation for two OD samples.