Editorial [Hot Topic: Cognition Therapeutics (Guest Editor: Miao-Kun Sun)]

Scientific research in cognition and cognitive pharmacology is entering an exciting era. Not only are we beginning through intensive investigations around the world, to better understand the synaptic and molecular mechanisms underlying cognition and cognitive disorders, but several therapeutic targets are also being examined for developing cognitive therapeutic agents and many more are starting to emerge. The excitement is best illustrated by the review articles in this hot topic theme issue of Current Drug Targets - CNS and Neurological Disorders. These articles cover important aspects of cognition therapeutics and therapeutic targets, including lowdensity lipoprotein receptor-related protein (LRP; by Harris-White and Frautschy), the cAMP responsive element binding protein (CREB; by Sheena A. Josselyn and Peter V. Nguyen), memantine for the glutamate hyperactivity (by Horst J. Koch, Gökhan Uyanik and David Fischer-Barnicol), the cannabinoid system (by Franjo Grotenhermen), the testosterone system (by E. Hogervorst and S.D. Moffat), the protein kinase C substrates (by Miao-Kun Sun and Daniel L. Alkon), cholesterol and the ApoE (by Daniela Fenili and JoAnne McLaurin), and Aβ removal/reduction (by Edith G. McGeer and Patrick L. McGeer). LRP is highly expressed in the pyramidal cells and plays an important role in synaptic transmission. LRP itself and its many ligands, including ApoE, α2-macroglobulin, the transforming growth factor-β , and the insulin-like growth factor, are important therapeutic targets in cognition and cognition disorders. Intracellular A accumulation leads to impaired neuronal metabolism and synaptic dysfunctions and is probably responsible for triggering the onset of cognitive dysfunction in Alzheimer's disease (AD). Therefore, blocking Aβ uptake and intracellular accumulation, including LRP-mediated neuronal uptake of ApoE-bound Aβ , has obvious therapeutic values in anti dementia therapy. The cAMP responsive element binding protein (CREB) represents another target in developing novel treatment of memory disorders. Cognition is impaired by many more pathogenic cascades, which serve as potential therapeutic targets. Glutamate hyperactivity, for instance, is involved in AD, vascular dementia, and other neurodegenerative disorders. Early findings also define an involvement of cholinergic deficits in AD. These studies have led to some antidementia drugs, such as cholinesterase inhibitors and memantine. Although these drugs are used clinically to treat AD patients, whether they can change over a long period, the rate of the disease progression is an entirely different issue. The cannabinoid system plays an important role in signal transduction. Its receptor agonists reduce Aβ neurotoxicity and thus possess an anti-AD action. The cannabinoid receptor1 antagonists, on the other hand, can improve memory in rats. Further studies are needed to evaluate potentials of the cannabinoid receptor agonists and antagonists in cognitive pharmacology. Effects of testosterone on cognition and cognitive disorders include a reduction in both Aβ formation and tau hyperphosphorylation, suggesting that the male hormone has a protective action against AD and cognitive decline. But further studies are required to define its long-term benefit. Protein kinase C activators have been found to produce several promising effects on AD and cognition, including an enhancement of spatial cognition, a reduction of Aβ formation and accumulation. Elevated cholesterol and the apolipoprotein E ε4 allele are important risk factors for AD. Immunization with Aβ , inhibitors of A formation, inhibitors of tau hyper-phosphorylation, cholesterol-lowering agents, β-sheet breaker peptides, and various miscellaneous agents and strategies presented in these review articles are currently the leading strategies in developing cognitive therapeutics. We hope that our efforts will be rewarded with new developments and facilitated emergence of therapeutic agents that are able to slow down or block the progression of cognitive disorders.