The γ-Secretase Modulator CHF5074 Restores Memory and Hippocampal Synaptic Plasticity in Plaque-Free Tg2576 Mice

Abstract

Abnormal amyloid-β (Aβ) production and deposition is believed to represent one of the main causes of Alzheimer's disease (AD). γ-Secretase is the enzymatic complex responsible for Aβ generation from its precursor protein. Inhibition or modulation of γ-secretase represents an attractive therapeutic approach. CHF5074 is a new γ-secretase modulator that has been shown to inhibit brain plaque deposition and to attenuate memory deficit in adult AD transgenic mice after chronic treatment. To date, it is not known whether the positive behavioral effects of this compound also occur in young transgenic mice without plaque deposition. Here, we evaluated the effects of acute and subchronic treatment with CHF5074 on contextual and recognition memory and on hippocampal synaptic plasticity in plaque-free Tg2576 mice. We found that at 5 months of age, contextual memory impairment was significantly attenuated after acute subcutaneous administration of 30 mg/kg CHF5074. At 6 months of age, recognition memory impairment was fully reversed after a 4-week oral treatment in the diet (≈60 mg/kg/day). These cognitive effects were associated with a reversal of long-term potentiation (LTP) impairment in the hippocampus. A significant reduction in brain intraneuronal AβPP/Aβ levels and hyperphosphorylated tau, but no change in soluble or oligomeric Aβ levels was detected in Tg2576 mice showing functional recovery following CHF5074 treatment. We conclude that the beneficial effects of CHF5074 treatment in young transgenic mice occurred at a stage that precedes plaque formation and were associated with a reduction in intraneuronal AβPP/Aβ and hyperphosphorylated tau.

c-Jun N-terminal kinase has a key role in Alzheimer disease synaptic dysfunction in vivo

“…Among them, there are controversial data regarding the modulation of the γ -secretase. The selective blocker CHF5074 of this enzyme restored synaptic plasticity in Tg2576 mice, 37 although it did not rescue synaptic defects in a mouse model of familial Danish dementia. 38 In addition, Chen et al 39 showed that an inhibitor of calcineurin completely prevented A β -induced LTP deficits in wt mice.…”

Reduction of β-amyloid and γ-secretase by calorie restriction in female Tg2576 mice

“…Pharmacological manipulation of γ-secretase function is an effective method for reducing Aβ pathology and has been applied to several AD clinical trials, although off-target effects have hampered study success, raising a question whether Aβ monotherapy is an effective treatment strategy (Crump et al, 2013; Golde et al, 2013; Mikulca et al, 2014). Despite these concerns, γ-secretase inhibition in the Tg2576 AD mouse model abrogates agedependent pathology indicators, including Aβ burden, spatial memory deficits, abnormal dendritic spine morphology, and microglial activation (Sivilia et al, 2013) and interestingly, also blunts early impairments in younger Tg2576 mice (Balducci et al, 2011). Furthermore, work by Placanica et al .…”

Chemical Modulators of Protein Misfolding, Neurodegeneration and Tau

“…Acute CHF5074 treatment on plaque-free, neurologically impaired 5-month-old TG mice (subcutaneous injections (s.c.), 10-30-100 mg/kg, 3 or 24 hr before behavioral testing) leads to dose-dependent memory improvement without altering the low Ab levels in TG mice [84]. Subchronic treatment (≈60 mg/kg daily, p.o., 4 weeks) shows full memory recovery and unchanged Ab levels [84]. Similar effects are observed with acute and subchronic treatment of 7-month-old TG mice (30 mg/kg, s.c., 3 or 24 hr before behavioral testing, and for 8 days) [85].…”