APLP2 is predominantly cleaved by ß-secretase and γ-secretase in the human brain.

BACKGROUND: Amyloid-ß peptide is well-known as a pathogen of Alzheimer's disease, but its precursor, amyloid-beta precursor protein (APP), remains unexplained 30 years after its discovery. APP has two homologues called amyloid precursor-like protein 1 (APLP1) and amyloid precursor-like protein 2 (APLP2), and shares a similar structural organisation with them and has partially overlapping functions. APP family proteins are essential for survival, shown by the crossbreeding analysis of knockout mice of APP family molecules, including APLP1 and APLP2. APLP2 is known to play the most important role among them, but the molecular metabolism of APLP2 is only partially understood. Here, we analysed ectodomain shedding and γ-secretase cleavage of APLP2 by molecular biological and biochemical techniques. METHOD: We analysed the culture supernatant of HEK293 cells overexpressing APLP2 and human cerebrospinal fluid. For the analysis of secreted APLP2 fragments, we raised the OA603 antibody that reacts with the juxtamembrane domain of APLP2. Substrate cleavage sites were identified by matrix assisted laser desorption/ionisation mass spectrometry. RESULTS: By overexpressing in HEK293 cells, APLP2 undergoes ectodomain shedding at three sites in the extracellular region by α- and ß-secretase-like activity and then is intramembranously cleaved at three sites by γ-secretase. In particular, in shedding, α-secretase-like activity was dominant in HEK cells. Surprisingly, in human cerebrospinal fluid, APLP2-derived metabolic fragments were mainly cleaved by ß-secretase-like activity, not by α-secretase-like activity. Because APP is also mainly cleaved by beta-site amyloid precursor protein cleaving enzyme 1 in neurons and APLP1 is expressed exclusively in neurons, these findings suggest that APP family proteins may play a common role via ß-secretase-like cleavage in the central nerve system. CONCLUSIONS: Thus, these findings may contribute to a better understanding of the role of APP family proteins in Alzheimer's disease.

Plasma NfL is associated with mild cognitive decline in patients with diabetes.

BACKGROUND: Patients with diabetes are at a higher risk for cognitive decline. Thus, biomarkers that can provide early and simple detection of cognitive decline are required. Neurofilament light chain (NfL) is a cytoskeletal protein that constitutes neural axons. Plasma NfL levels are elevated when neurodegeneration occurs. Here, we investigated whether plasma NfL levels were associated with cognitive decline in patients with type 2 diabetes. METHOD: This study included 183 patients with type 2 diabetes who visited Osaka University Hospital. All participants were tested for cognitive function using the Mini-Mental State Examination (MMSE) and the Rivermead Behavioural Memory Test (RBMT). NfL levels were analysed in the plasma and the relationship between NfL and cognitive function was examined. RESULTS: Lower RBMT-standardized profile scores (SPS) or MMSE scores correlated with higher plasma NfL levels (one-way analysis of variance: MMSE, P = 0.0237; RBMT-SPS, P = 0.0001). Furthermore, plasma NfL levels (ß = -0.34, P = 0.0005) and age (ß = -0.19, P = 0.016) were significantly associated with the RBMT score after multivariable regression adjustment. CONCLUSIONS: Plasma NfL levels were correlated with mild cognitive decline which is detected by the RBMT but not the MMSE in patients with type 2 diabetes. This suggests that plasma NfL levels may provide a valuable clinical tool for identifying mild cognitive decline in patients with diabetes.

Renal function is associated with blood neurofilament light chain level in older adults.

Neurofilament light chain (NfL) is a novel biomarker of neurodegenerative diseases. It is detectable in the peripheral blood, allowing low-invasive assessment of early signs of neurodegeneration. The level of NfL gradually increases with age; however, what other factors affect it remains unclear. The present study examined the association between blood NfL level and renal function among healthy participants undergoing a health check (n = 43, serum NfL) and patients with diabetes mellitus (n = 188, plasma NfL). All participants were 60 years of age or older; none were diagnosed with dementia. In each group, levels of blood NfL and serum creatinine significantly correlated (coefficient r = 0.50, 0.56). These associations remained statistically significant even after adjustment for age, sex, and body mass index. These findings indicate that blood NfL level might be partially affected by renal function. We recommend measuring renal function for a more precise evaluation of neuroaxonal damage, in particular, among older adults.