Alzheimer's disease (AD) is the most common form of dementia among the elderly. In AD patients, memory loss is accompanied by the formation of beta-amyloid plaques and the appearance of tau in a pathological form. Given the lack of effective treatments for AD, the development of new management strategies for these patients is critical. The continued failure to find effective therapies using molecules aimed at addressing the anti-beta amyloid pathology has led researchers to focus on other non-amyloid-based approaches to restore memory function. Promising non-amyloid related candidate targets include phosphosdiesterases (PDEs), and indeed, Rolipram, a specific PDE4 inhibitor, was the first compound found to effectively restore cognitive deficits in animal models of AD. More recently, PDE5 inhibitors have also been shown to effectively restore memory function. Accordingly, inhibitors of other members of the PDE family may also improve memory performance in AD and non-AD animal models. Hence, in this review, we will summarize the data supporting the use of PDE inhibitors as cognitive enhancers and we will discuss the possible mechanisms of action underlying these effects. We shall also adopt a medicinal chemistry perspective that leads us to propose the most promising PDE candidates on the basis of inhibitor selectivity, brain distribution, and mechanism of action.

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BACKGROUND AND PURPOSE Inhibitors of phosphodiesterase 5 (PDE5) affect signalling pathways by elevating cGMP, which is a second messenger involved in processes of neuroplasticity. In the present study, the effects of the PDE5 inhibitor, sildenafil, on the pathological features of Alzheimer's disease and on memory‐related behaviour were investigated. EXPERIMENTAL APPROACH Sildenafil was administered to the Tg2576 transgenic mouse model of Alzheimer's disease and to age‐matched negative littermates (controls). Memory function was analysed using the Morris water maze test and fear conditioning tasks. Biochemical analyses were performed in brain lysates from animals treated with saline or with sildenafil. KEY RESULTS Treatment of aged Tg2576 animals with sildenafil completely reversed their cognitive impairment. Such changes were accompanied in the hippocampus by a reduction of tau hyperphosphorylation and a decrease in the activity of glycogen synthase kinase 3β (GSK3β) and of cyclin‐dependent kinase 5 (CDK5) (p25/p35 ratio). Moreover, sildenafil also increased levels of brain‐derived neurotrophic factor (BDNF) and the activity‐regulated cytoskeletal‐associated protein (Arc) in the hippocampus without any detectable modification of brain amyloid burden. CONCLUSIONS AND IMPLICATIONS Sildenafil improved cognitive functions in Tg2576 mice and the effect was not related to changes in the amyloid burden. These data further strengthen the potential of sildenafil as a therapeutic agent for Alzheimer's disease.

Insulin-like growth factor 2 (IGF2) was recently found to play a critical role in memory consolidation in rats and mice, and hippocampal or systemic administration of recombinant IGF2 enhances memory. Here, using a gene therapy-based approach with adeno-associated virus (AAV), we show that IGF2 overexpression in the hippocampus of aged wild-type mice enhances memory and promotes dendritic spine formation. Furthermore, we report that IGF2 expression decreases in the hippocampus of patients with Alzheimer's disease, and this leads us to hypothesize that increased IGF2 levels may be beneficial for treating the disease. Thus, we used the AAV system to deliver IGF2 or IGF1 into the hippocampus of the APP mouse model Tg2576 and demonstrate that IGF2 and insulin-like growth factor 1 (IGF1) rescue behavioural deficits, promote dendritic spine formation and restore normal hippocampal excitatory synaptic transmission. The brains of Tg2576 mice that overexpress IGF2 but not IGF1 also show a significant reduction in amyloid levels. This reduction probably occurs through an interaction with the IGF2 receptor (IGF2R). Hence, IGF2 and, to a lesser extent, IGF1 may be effective treatments for Alzheimer's disease.

These results support the potential involvement of cGMP in the pathological and clinical development of AD. The cGMP reduction in early stages of AD might participate in the aggravation of amyloid pathology and cognitive decline.

The targeting of two independent but synergistic enzymatic activities, histone deacetylases (HDACs, class I and HDAC6) and phosphodiesterase 5 (PDE5), has recently been validated as a potentially novel therapeutic approach for Alzheimer's disease (AD). Here we report the discovery of a new first-in-class small-molecule (CM-414) that acts as a dual inhibitor of PDE5 and HDACs. We have used this compound as a chemical probe to validate this systems therapeutics strategy, where an increase in the activation of cAMP/cGMPresponsive element-binding protein (CREB) induced by PDE5 inhibition, combined with moderate HDAC class I inhibition, leads to efficient histone acetylation. This molecule rescued the impaired long-term potentiation evident in hippocampal slices from APP/PS1 mice. Chronic treatment of Tg2576 mice with CM-414 diminished brain Aβ and tau phosphorylation (pTau) levels, increased the inactive form of GSK3β, reverted the decrease in dendritic spine density on hippocampal neurons, and reversed their cognitive deficits, at least in part by inducing the expression of genes related to synaptic transmission. Thus, CM-414 may serve as the starting point to discover balanced dual inhibitors with an optimal efficacy and safety profile for clinical testing on AD patients.

Simultaneous inhibition of phosphodiesterase 5 (PDE5) and histone deacetylases (HDAC) has recently been validated as a potentially novel therapeutic approach for Alzheimer's disease (AD). To further extend this concept, we designed and synthesized the first chemical series of dual acting PDE5 and HDAC inhibitors, and we validated this systems therapeutics approach. Following the implementation of structure- and knowledge-based approaches, initial hits were designed and were shown to validate our hypothesis of dual in vitro inhibition. Then, an optimization strategy was pursued to obtain a proper tool compound for in vivo testing in AD models. Initial hits were translated into molecules with adequate cellular functional responses (histone acetylation and cAMP/cGMP response element-binding (CREB) phosphorylation in the nanomolar range), an acceptable therapeutic window (>1 log unit), and the ability to cross the blood-brain barrier, leading to the identification of 7 as a candidate for in vivo proof-of-concept testing ( Cuadrado-Tejedor, M.; Garcia-Barroso, C.; Sánchez-Arias, J. A.; Rabal, O.; Mederos, S.; Ugarte, A.; Franco, R.; Segura, V.; Perea, G.; Oyarzabal, J.; Garcia-Osta, A. Neuropsychopharmacology 2016 , in press, doi: 10.1038/npp.2016.163 ).

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