Neurobiology of Disease (Oct 2022)
Apolipoprotein L1 is increased in frontotemporal lobar degeneration post-mortem brain but not in ante-mortem cerebrospinal fluid
Abstract
Aims: Frontotemporal Dementia (FTD) is caused by frontal-temporal lobar degeneration (FTLD), characterized mainly by brain protein aggregates of tau (FTLD-Tau) or TDP-43 (FTLD-TDP). The clinicopathological heterogeneity makes ante-mortem diagnosis of these pathological subtypes challenging. Our proteomics study showed increased Apolipoprotein L1 (APOL1) levels in CSF from FTD patients, which was prominently expressed in FTLD-Tau. We aimed to understand APOL1 expression in FTLD post-mortem brain tissue and to validate its potential as a CSF biomarker for FTD and its pathological subtypes. Methods: APOL1 levels were analyzed in the frontal cortex of FTLD (including FTLD-Tau and FTLD-TDP) and non-demented controls by immunohistochemistry (FTLD total = 18 (12 FTLD-Tau and 6 FTLD-TDP); controls = 9), western blot (WB), and a novel prototype ELISA (FTLD total = 44 (21 FTLD-Tau and 23 FTLD-TDP); controls = 9). The association of APOL1 immunoreactivity with phosphorylated Tau (pTau) and TDP-43 (pTDP-43) immunoreactivity was assessed. CSF APOL1 was analyzed in confirmed FTD patients (n = 27, including 12 FTLD-Tau and 15 FTLD-TDP) and controls (n = 15) using the same ELISA. Results: APOL1 levels were significantly increased in FTLD post-mortem tissue compared to controls as measured by immunohistochemistry, WB, and ELISA. However, no differences between the pathological subtypes were observed. APOL1 immunoreactivity was present in neuronal and glial cells but did not co-localize with pTau or pTDP-43. CSF APOL1 levels were comparable between FTD patients and controls and between pathological subtypes. Conclusion: APOL1 is upregulated in FTLD pathology irrespective of the subtypes, indicating a role of this novel protein in FTD pathophysiology. The APOL1 levels detected in brain tissue were not mirrored in the CSF, limiting its potential as a specific FTD biofluid-based biomarker using our current immunoassay.
