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Background/Aims: Impaired mitochondrial function has been described in Alzheimer’s disease. We previously reported that, in neuronal cells, β-amyloid 1–42 (Aβ_1–42) is targeted to mitochondria. We have also reported that, when incubated with isolated rat brain mitochondria, Aβ_1–42 inhibits complex IV, uncouples the mitochondrial respiratory chain, and promotes opening of the membrane permeability transition pore. Here, we further analyzed the targeting and mitotoxicity of Aβ_1–42. Methods and Results: Immunoelectron microscopy revealed that the mitochondrial targeting of Aβ_1–42 was concentration- and time-dependent. Incubation of human neuroblastoma cells with Aβ_1–42 increased the release of adenylate kinase, a mitochondrial enzyme released after membrane permeability transition pore opening. However, it failed to trigger DNA fragmentation and apoptosis, suggesting that the ability of this peptide to uncouple the respiratory chain underlies its mitotoxicity and cytotoxicity. Aβ_1–42 targeting to mitochondria was blocked by caprospinol, a steroid derivative shown to protect neuronal cells against Aβ_1–42-induced neurotoxicity. Further experiments revealed that the mitotoxic effect of Aβ_1–42 is specific to its primary amino acid sequence and suggested that it may be also related to its tertiary structure. Importantly, the mitotoxic effect of Aβ_1–42 was not restricted to brain cells, indicating that it is not cell- or tissue-specific. Conclusion: Taken together, these results suggest that extracellular Aβ_1–42 targets neuronal mitochondria to exert its toxic effects.

We report herein the synthesis and biological evaluation of dimethyl-carbamic acid 2,3-bis-dimethylcarbamoyloxy-6-(4-ethyl-piperazine-1-carbonyl)-phenyl ester (SP-04), a new drug candidate that is designed to offer a multi-target therapeutic neuroprotective approach as a treatment for Alzheimer's disease (AD). SP-04 inhibits acetylcholinesterase (AchE) activity both in vitro and in vivo, and induces a dose-dependent increase in Ach levels. SP-04 releases the metabolite 4-(4-ethyl-piperazin-1-yl)-1-(2,3,4-trihydroxy-phenyl)-butan-1-one (SP-04m). Both SP-04 and SP-04m are s1-receptor antagonists supporting their interest in relieving symptoms related to psychosis, a non-cognitive condition often associated with AD. SP-04m displays important antioxidant properties and both SP-04 and SP-04m offers neuroprotection against Ab42 toxicity in various neuronal cell lines. In addition, both SP-04 and SP-04m protect neuronal cells and rat brain mitochondria exposed to various mitochondrial respiratory chain complex toxins. Taken together these data suggest that the SP-04 multi-targeting approach might offer a novel therapeutic strategy for the treatment of AD.