Carles_2024_CNS.Neurosci.Ther_30_e14814

AIMS: Alzheimer's disease (AD) is a devastating dementia characterized by extracellular amyloid-beta (Abeta) protein aggregates and intracellular tau protein deposition. Clinically available drugs mainly target acetylcholinesterase (AChE) and indirectly sustain cholinergic neuronal tonus. Butyrylcholinesterase (BChE) also controls acetylcholine (ACh) turnover and is involved in the formation of A aggregates and senile plaques. UW-MD-95 is a novel carbamate-based compound acting as a potent pseudo-irreversible BChE inhibitor, with high selectivity versus AChE, and showing promising protective potentials in AD. METHODS: We characterized the neuroprotective activity of UW-MD-95 in mice treated intracerebroventricularly with oligomerized Abeta(25-35) peptide using behavioral, biochemical, and immunohistochemical approaches. RESULTS: When injected acutely 30 min before the behavioral tests (spontaneous alternation in the Y-maze, object recognition, or passive avoidance), UW-MD-95 (0.3-3 mg/kg) showed anti-amnesic effects in Abeta(25-35)-treated mice. When injected once a day over 7 days, it prevented Abeta(25-35)-induced memory deficits. This effect was lost in BChE knockout mice. Moreover, the compound prevented Abeta(25-35)-induced oxidative stress (assessed by lipid peroxidation or cytochrome c release), neuroinflammation (IL-6 and TNFalpha levels or GFAP and IBA1 immunoreactivity) in the hippocampus and cortex, and apoptosis (Bax level). Moreover, UW-MD-95 significantly reduced the increase in soluble Abeta(1-42) level in the hippocampus induced by Abeta(25-35). CONCLUSION: UW-MD-95 appeared as a potent neuroprotective compound in the Abeta(25-35) model of AD, with potentially an impact on Abeta(1-42) accumulation that could suggest a novel mechanism of neuroprotection.