Nivegacetor, a gamma secretase modulator, shifts Aβ production to shorter, non-amyloidogenic isoforms in vitro and in mice.

Alzheimer's Disease (AD) is a complex neurodegenerative disorder characterized by the accumulation of amyloid-beta (Aβ) peptides. Specifically, longer isoforms like Aβ42 are highly neurotoxic and prone to aggregation, driving much of the pathology. Current treatments often fall short in halting disease progression. Aβ peptides are generated by sequential cleavage of amyloid precursor protein (APP) by β-secretase (BACE1) and γ-secretase. Gamma secretase modulators (GSMs) offer a promising strategy by shifting γ-secretase activity to produce shorter, non-amyloidogenic Aβ peptides (e.g., Aβ37, Aβ38) instead of the harmful longer ones.

Researchers evaluated the novel GSM nivegacetor in vitro using cell lines overexpressing human wild-type APP or human APP with the Swedish mutation APPSwe. In vitro selectivity was assessed against Notch-1, another γ-secretase substrate, and a broad panel of pharmacological targets. In vivo studies investigated the dose-response and time course of nivegacetor on soluble Aβ levels in brain tissue of APPSwe transgenic mice. The impact of two ADAD mutations, PSEN1 E280A and PSEN2 N141I, on nivegacetor's potency was also tested. Finally, nivegacetor was examined for potential interference with [3H]florbetaben binding to Aβ plaques in human AD brain tissue sections.

Nivegacetor demonstrated a potent and selective modulation of γ-secretase activity. It consistently lowered the production of neurotoxic Aβ42 and Aβ40 while concomitantly increasing levels of the shorter, non-amyloidogenic Aβ37 and Aβ38 peptides. This effect was observed both in vitro in cell lines and in vivo in APPSwe transgenic mice. Crucially, nivegacetor did not inhibit Notch-1 cleavage, indicating a favorable selectivity profile over pan-γ-secretase inhibitors, and showed high selectivity across a broad range of other pharmacological targets. When tested against familial AD mutations, nivegacetor was equipotent on the PSEN1 E280A mutation but was significantly less potent on the PSEN2 N141I mutation compared to wild-type γ-secretase. Importantly, nivegacetor did not interfere with the detection of amyloid plaques by [3H]florbetaben in human AD brain tissue, a critical factor for clinical imaging.

Nivegacetor lowered the production of Aβ42 and Aβ40 and concomitantly increased levels of Aβ37 and Aβ38 in vitro and in vivo in mice.