Caffeine increases mitochondrial function and blocks melatonin signaling to mitochondria in Alzheimer's mice and cells

Caffeine and melatonin have been shown to protect the Swedish mutant amyloid precursor protein (APPsw) transgenic mouse model of Alzheimer's disease from cognitive dysfunction. But their mechanisms of action remain incompletely understood. These Alzheimer's mice have extensive mitochondrial dysfunction, which likely contributes to their cognitive decline. To further explore the mechanism through which caffeine and melatonin protect cognitive function in these mice, we monitored the function of isolated mitochondria from APPsw mice treated with caffeine, melatonin, or both in their drinking water for one month. Melatonin treatment yielded a near complete restoration of mitochondrial function in assays of respiratory rate, membrane potential, reactive oxygen species production, and ATP levels. Caffeine treatment by itself yielded a small increase in mitochondrial function. However, caffeine largely blocked the large enhancement of mitochondrial function provided by melatonin. Studies with N2a neuroblastoma cells stably expressing APPsw showed that specific inhibition of cAMP-dependent phosphodiesterase (PDE) 4 or cGMP-dependent PDE5 also blocked melatonin protection of mitochondrial function, but A2a and A1 adenosine receptor antagonists were without effect. Melatonin or caffeine at the concentrations used to modulate mitochondrial function in the cells had no effect on cAMP-dependent PDE activity or cellular cAMP or cGMP levels. Therefore, caffeine and increased cyclic nucleotide levels likely block melatonin signaling to mitochondria by independent mechanisms that do not involve adenosine receptor antagonism. The results of this study indicate that melatonin restores mitochondrial function much more potently than caffeine in APPsw transgenic mouse and cell models of Alzheimer's disease.

► Melatonin restored mitochondrial function in APPsw Alzheimer's mice.
► Caffeine slightly increased mitochondrial function in APPsw mice.
►  Caffeine blocked the melatonin-induced restoration of mitochondrial function.
► Inhibiting PDE4 or PDE5 blocked melatonin restoration of mitochondrial function.
► Caffeine blocked melatonin's signal to mitochondria without affecting PDE activity.