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- W2895788388 abstract "The β-site amyloid precursor protein-cleaving enzyme (BACE1) constitutes a major target for the potential treatment of Alzheimer's disease. Previous studies have shown, that long-term inhibition of BACE1 not only prevents amyloid-beta (Aβ) production and deposition but also suppresses the neurofilament light chain (NfL) increase in the cerebrospinal fluid (CSF) of amyloid precursor protein (APP) transgenic mice during the initial phase of cerebral β-amyloidosis (Bacioglu et al., Neuron 2016). CSF NfL is assumed to be a promising biomarker for neurodegeneration. However, it is not known whether BACE inhibition can also block the CSF NfL increase in APP transgenic mice at a later stage of amyloid pathology. APPPS1 transgenic mice (Radde et al., EMBO Rep 2006) were treated with a potent BACE1 inhibitor for 3 months at an early, intermediate or late stage of Aβ deposition (1.5, 12, or 18 months, respectively). After the treatment, brain Aβ and CSF NfL levels were assessed using stereological quantification and sandwich immunoassays. Measurements were compared to non-treated littermates and baseline controls. BACE1 inhibitor treatment at 1.5 months of age largely prevented Aβ deposition and concomitantly suppressed the CSF NfL increase. Treatment at an intermediate stage similarly prevented both brain Aβ and CSF NfL increase. In aged transgenic mice, i.e. at the plateau phase of Aβ deposition, BACE1 treatment was able to reduce brain Aβ below baseline but CSF NfL increased. Results demonstrate that CSF NfL levels are tightly connected to β-amyloidosis at early stages of pathogenesis but become independent from Aβ increase at late stages of β-amyloidosis. These observations suggest that Aβ aggregation triggers a neurodegenerative process that at later time points, when Aβ deposition reaches a plateau, becomes independent from Aβ increase. These findings imply that BACE1 inhibitors in clinical trials are most effective in AD patients with low or moderate Aβ burden and become arguably less valid in a more progressed phase of the disease." @default.
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- W2895788388 date "2018-07-01" @default.
- W2895788388 modified "2023-10-16" @default.
- W2895788388 title "P1‐116: NEUROFILAMENT LIGHT LEVELS IN THE CEREBROSPINAL FLUID ARE UNCOUPLED OF AMYLOIDOSIS IN LATE STAGE PATHOGENESIS OF APP TRANSGENIC MICE" @default.
- W2895788388 doi "https://doi.org/10.1016/j.jalz.2018.06.119" @default.
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