Introduction: Phosphodiesterase (PDE) inhibitors improve signaling pathways in brain circuits by increasing intracellular cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP). In the last decade, the first clinical studies investigating selective PDE inhibitors in Alzheimer’s disease (AD) have been initiated, based on their positive effects on cognitive processes and neuroprotection in numerous animal studies. Areas covered: This article reviews the clinical studies investigating the pro-cognitive/neuroprotective effects of PDE inhibitors in patients with AD, as well as in age-associated memory impaired elderly and patients with mild cognitive impairment (MCI), the prodromal stage of AD. PDE inhibitors will also be discussed with respect to adverse effects including safety and tolerability. Expert opinion: The limited available data of clinical studies with PDE inhibitors tested in different populations of AD patients do not allow the drawing of any concrete conclusion yet. Currently, studies with a PDE3 (cilostazol) or PDE9 inhibitor (BI 409,306) are still ongoing in patients with MCI or AD, respectively. Studies with PDE4 inhibitors (HT-0712, roflumilast and BPN14770) in healthy elderly and elderly with age-associated memory impairments indicate that the optimum dose and/or inhibiting the most relevant PDE isoform hold great promise when tested in the appropriate population of patients with MCI or AD eventually.

Phosphodiesterase inhibitors (PDE-Is) enhance cAMP and/or cGMP signaling via reducing the degradation of these cyclic nucleotides. Since both cAMP and cGMP signaling are essential in a variety of cellular functions, including neuroplasticity and neuroprotection, PDE-Is are receiving increased attention as possible targets for treatment of age-related cognitive decline as well as Alzheimer’s disease (AD). In this review we will give a translational overview of the preclinical and clinical data on PDE-Is and cognition enhancement focusing on aging and AD. PDE2, 4 and 5 inhibitors improved memory performance in both aged animals and models of AD. Treatment with a PDE3-I or PDE7-I has not been tested in aged animals yet, but in mouse models of AD both PDE-Is improved memory performance. Unfortunately, there are no peer-reviewed studies on the effects of PDE-I treatment in aged human subjects except the possible positive effect on memory impairment of the PDE1-I vinpocetine. Three other types of PDE-Is have been tested on cognition in mild to moderate AD patients: the PDE3-I cilostazol is being tested as a co-treatment to the acetylcholinesterase inhibitor donepezil, but with inconsistent results; the PDE4-I MK-0952 has been tested, although the outcome has not been disclosed yet; and the PDE9-I PF- 04447943 was reported to have no effects on cognition. Obviously, the demonstration of clinical proof of concept for cognition enhancing effects of PDE-Is and the generation of isoform selective PDE-Is are the final hurdles to overcome in developing safe and efficacious novel PDE-Is for the treatment of age-associated cognitive decline or AD.

Oligodendrocytes provide metabolic and functional support to neuronal cells, rendering them key players in the functioning of the central nervous system. Oligodendrocytes need to be newly formed from a pool of oligodendrocyte precursor cells (OPCs). The differentiation of OPCs into mature and myelinating cells is a multistep process, tightly controlled by spatiotemporal activation and repression of specific growth and transcription factors. While oligodendrocyte turnover is rather slow under physiological conditions, a disruption in this balanced differentiation process, for example in case of a differentiation block, could have devastating consequences during ageing and in pathological conditions, such as multiple sclerosis. Over the recent years, increasing evidence has shown that epigenetic mechanisms, such as DNA methylation, histone modifications, and microRNAs, are major contributors to OPC differentiation. In this review, we discuss how these epigenetic mechanisms orchestrate and influence oligodendrocyte maturation. These insights are a crucial starting point for studies that aim to identify the contribution of epigenetics in demyelinating diseases and may thus provide new therapeutic targets to induce myelin repair in the long run.