###### Abstract  
[PERSON]'s disease is a memory-related neurodegenerative condition leading to cognitive impairment. Cholinergic deficit, together with other underlying mechanisms, leads the to onset and progression of the disease. Consequently, acetylcholinesterasecholinesteraseaires are used for the symptomatic treatment of dementia, even if limited efficacy is observed. More recently, some specific phosphodiesteraseer isoforms emerged as promising, alternative targets for developing inhibitors to contrast neurodegeneration. Phosphodiesterase isoforms 4, 5 and 9 were found to be expressed in brain regions that are relevant for cognition. Given the complex nature of [PERSON]'s disease and the combination of involved biochemical mechanisms, the development of polypharmacological agents acting on more than one pathway is desirable. This review provides an overview of recent reports focused on natural and Nature-inspired small molecules, or plant extracts, acting as dual cholinesterase and phosphodiesteraseer inhibitors. In the context of the multi-target directed ligand approach, such molecules would pave the way for the development of novel agents against neurodegeneration. More precisely, according to the literature data, xanthines, other alkaloids, flavonoids, coumarins and polyphenic acids represent promising scaffolds for future optimization. Alzheimer's disease; acetylcholinesterasecholinesteraseerase; phosphodiesteraseerase; multi-target directed ligand; polypharmacology; natural compounds +
Footnote †: journal: Medical  
monophosphate (cGMP)-selective isoform, is upregulated in the brains of AD patients, and its functioning influences neuronal plasticity. Several PDE5 inhibitors, such as tadalafil (Figure 1b), are being studied for their applications against dementia in the context of drug repurposing [8,15]. Eventually, PDE9A, which selectively hydrolyzes cGMP, is expressed in brain regions that are relevant for cognition and, thus, is recently receiving more attention [16,17]. The efficacy of selective PDE9 inhibitors, such as BAY 736691, PF-0447943 and BI 409306, was proved in preclinical and clinical studies [18, 19, 20]. Thus, since PDE4, PDE5 and PDE9 isoforms are involved in the nitric oxide (NO) signaling cascade, which includes NON-sensitive guanylyl cyclase and protein kinase G, in improving neuronal plasticity via cAMP responsive element binding (CREB) protein activation, in maintaining the efficiency of neuronal vascularization and in glutamate release, the action of selective PDE inhibitors could represent an alternative and complementary approach to contrast dementia [7,8]. As anticipated, given the complex nature of AD and the combination of multiple biochemical mechanisms underlying onset and progression of this disease, the development of polyfunctional therapeutic agents acting on more than one pathway is desirable, and natural compounds are historically endowed with polypharmacological features [3,21,22]. In medicinal chemistry, the multi-target directed ligand (MTDL) approach is being pursued with the same aim [15]. In this context, this review is focused on natural and Nature-inspired small molecules, or plant extracts, acting at the same time as AChE and PDE inhibitors, and thus with a potential application in contrasting neurodegeneration. More than 70 research papers and reviews were screened for the preparation of the current article. Scientific contributions were retrieved by searching PubMed (www.ncbi.nlm.nih.gov/pubmed/ (accessed on 25 March 2021)) and Scopus (www.scopus.com (accessed on 25 March 2021)) databases using keywords such as \"phosphodiesterase\", \"PDE4\", \"PDE5\", \"PDE9\", \"acetylcholinesteraseterase\", \"butyrylcholinesteraseterase\", \"natural compounds\", \"neurodegeneration\", \"Alzheimer's disease\" and their combinations. Papers published in the 2000-2021 timeframe were considered. The 3D models of the studied protein and  
Figure 1: 3D structures of AChE in complex with donepezil (**a**, PDB ID: 4 EY7) and of PDE5 in complex with tadalafil (**b**, PDB ID: 1 UDU).