Neprilysin Activity in Cerebrospinal Fluid is Associated with Dementia and Amyloid-β 42 Levels in Lewy Body Disease

Abstract

Lewy body disease, defined by the occurrence of α-synuclein aggregates as fibrils in Lewy bodies and Lewy neurites, is associated with increased probabilities for both co-occurrence of dementia, and co-occurrence of Alzheimer's disease (AD)-like pathology, in particular amyloid-β (Aβ) plaques and lowered cerebrospinal fluid (CSF) Aβ₄₂ levels. Not surprisingly, in patients with Lewy body disease patients, there is a strong association between dementia and Aβ₄₂ pathology. Neprilysin (NEP) is an Aβ-degrading protein found at presynaptic terminals and in body fluids. Reduced CSF NEP activity levels have been shown to occur in early AD, suggesting that altered CSF NEP activity levels may also be associated with dementia and lowered CSF Aβ₄₂ levels in Lewy body disease. Hypothesizing a relation between CSF NEP activity and dementia in Lewy body disease, we determined CSF and serum NEP activity, and Aβ₄₂ levels of 41 demented Lewy body disease patients, 38 non-demented Lewy body disease patients, and of 23 elderly controls. Demented Lewy body disease patients had lowered CSF NEP activity levels (0.3 pmol/min*ml, 0.2–81.5), compared to both non-demented Lewy body disease subjects (8.5 pmol/min*ml, 0.2–87.2; p = 0.004) and controls (21.5 pmol/ml*min, 0.15–413.4; p = 0.02). In addition, CSF NEP activity levels correlated positively with CSF Aβ₄₂ levels (Rho = 0.28, p = 0.008) which was not explained by the presence or absence of ApoE4. Serum NEP activity levels were not significantly different between the groups. We conclude that, in Lewy body disease, CSF NEP activity levels are associated with dementia, probably via the Aβ pathway.